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The Central Nervous System

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Chapter 1

Introduction

The central nervous system (CNS) mainly exchanges sensory receptor activity into many suitable behaviors for muscle activity. For these exchanges to occur there is a requirement of two balanced processes; the basis of building a simple but effective network connections and a fully functional mechanism that can simultaneously have an ability to constantly improve these connections. In neurobiology the identification of these mechanisms and structures also the changes are the objectives.

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The gathered evidence was on the specific contact site; the excitatory synapses on dendritic spines, the location of connective plasticity occurrence. Further understanding indicates on the basis of actin filaments the common mechanism; the formation of dendritic spines and mature synapse structural plasticity (Matus, 2000).

A typical nerve cell has a cell body or soma that contains a nucleus, dendrites and an axon. Dendrites are tree like branched extensions of the nerve cell, branching up to a hundred micrometers to give a morphological likeness of a tree. These nerve cells processes and relays information by electrical and chemical signaling. The neurons are capable of maintaining a voltage gradient across their membrane. This is carried out by metabolically motivated ion pumps, which are associated with ion channels. Ions that are associated in this metabolic action are sodium, potassium, chloride and calcium. Changes in these ion concentrations also change the function of the ion channels. Chemical signaling is the process that occurs by synapses that allow signals to be passed onto another cell or target cells.

Chemical synapse; neurotransmitters are released that bind to receptors of the postsynaptic cell. The transmission link of neurons in the brain solely through structural components called synapses. From extensive and multiple experiments carried out on dendrites came about the fundamental understanding of dendrites in neurons and the pathway of electrical and chemical signaling. In an observational view the morphology of dendrites and the local to long-range signals between other dendritic spines, thus giving the essential input-output interactions. From these electrical and optical recording studies showed the diverse signaling of dendrites and how they implement specific functions within the neuronal network (Hausser et al, 200

It has been known for a very long time that messenger Ribonucleic Acids (mRNAs) go through the transcription phase. The mRNA is the key player in the process of protein synthesis. This goes through the process of transportation, followed by translation. By the end of the process a

specific synthesised protein is created to implement a specific function. They are transported into the dendrites via the microtubules towards the synapse. At this point a signal is required for translation of mRNA by a synaptic signal or stimuli. This stimulation or signal; synthesises proteins that is specifically required in that particular region of the synapse (Pinkstaff et al, 2001).

Dendritic mRNA have been studied and scientifically analysed for their regulatory functions. Various transcripts are unique in their own special way depending on the type of neuron class; therefore different neurons convey different types of dendritic mRNAs. Postsynaptic density (PSD) of excitatory synapses has over 300 different proteins accumulated in many diverse complexes. It is not unusual for dendritic mRNA to encode a vast array of proteins. Neurotransmitter receptors and signal transducing enzymes are produced by dendritic mRNA. More surprising secretory proteins such as tissue plasminogen activator (tPA) and Matrix Metalloproteinase 9 (MMP9) are also encoded by dendritic mRNAs.

The distribution between the neuronal dendrites and axon of mRNA are well established; so they are present on the dendrites as well as on the axons. What really baffles scientists is how they are transported to the destination. However what scientists know; are the complexity of neuronal dendrites and the localisation process of mRNA. Due to this it requires multiple mRNA binding protein of which of three are RNA-containing granules. These RNA containing granules are; ribonucleoprotein particles (RNPs), stress granules (SGs) and processing bodies (PBs). It has been universally accepted that majority of the mRNA are transported to dendrites as large group of RNPs theoretically said but as yet not verified specifically. However on the basis of RNPs role suggest that mRNA is transported in a dormant state. Consequently for a specific mRNA to be targeted dendritically; it must be gathered from the translation compartments usually in the nucleus (cell body) and then organised into RNPs. The proteins remain attached to the mRNA until it reaches its dendritic destination (Bramham et al, 2007).

Individual dendrites of neurons in the nervous system are communicated by thousands of interconnected synaptic terminals that signal information back and fourth of its surroundings. On each synaptic termina of postsynaptic membrane is the main designated area where firstly the information is initiated where the dendrites come together. Here the postsynaptic membrane of the synapse; regulated precisely of the strength of the synaptic transmission where neurotransmitter receptors attached to large protein based signaling mechanism. This signaling machine or mechanism is referred to as the postsynaptic density. The postsynaptic density helps the process of the information and the formation of memories of specific transmissions in accordance of the synaptic force by the response of the neural action (Kennedy, 2000).

The localisation of mRNA is determined how proteins are synthesised and regulated. The discovery of polyribosomes under the postsynaptic areas on dendrites, synapse associated polyribosomes are prevalent during the process when new synapse growth occurs (Steward, 1994). The polyribosomes gave the first and strong indication that translations of protein synthesis continued in dendrites. Furthermore the location of the polyribosomes led to the acknowledgement of the proteins synthesised is the main constituent of synapses and synaptic activity regulating the synthesis. Experiments using Immunohistochemical analysis practically indentified all the translational mechanisms associated for protein synthesis in dendrites. Those that were found included mRNAs, translation factors, ER (endoplasmic reticulum) and the Golgi body. Simultaneously mRNA from dendrites gave indications to the functions of protein synthesis. By doing further in situ hybridisation indentified more mRNA in dendrites by experimenting from different rat and mice neurons (Jiang et al, 2002).

Chapter 2 The Postsynaptic Density

In the central nervous system there a many synaptic connections that contain a well established structure called the postsynaptic density (PSD). A matter of dense protein attached to the postsynaptic membrane that sits in close proximity opposite of the presynaptic active area. The appearance of the postsynaptic densities varies from different regions. The thickness of each dense region are between 20-60nm, the denseness seems to cover the whole area of the postsynaptic surface. Occasionally they have dense sections that are thin and irregular sections. During the research on PSDs scientists have termed them as type 1 PSDs (I PSDs) and type 2 PDSs (II PSDs). The type1 PDSs are generally involved in excitatory properties in synapses. Type2 PSDs are those involved with inhibitory properties in the synapses. It is thought that PSDs contain diverse proteins that have specific functions related to transmitter receptor type (Kennedy et al, 1983).

The proteins associated with the postsynaptic density are; scaffold proteins, cytoskeletal proteins, signaling proteins. The signaling proteins interact with glutamate receptors also postsynaptic membrane proteins for structural and functional purposes. PSD consists of an array of interacting proteins right under the postsynaptic membrane. The scaffold proteins attach and bind glutamate receptors, signaling pathways and to cytoskeletal associated structures (Romorini et al, 2004).

The postsynaptic density undergoes alteration in long-term changes; if the resultant stimulation is applied to the synapse and the change occurs to the synapse structure. It has also been foretold that if the structures changes occur by the concentration and the conformation of the proteins associated with the postsynaptic density. That also leads to changes in physiology of dendritic spines and to a certain extent the presynaptic junction. The dense matter of the postsynaptic density is only found in tissues associated with the central nervous system; complexity of the network array of neuronal cells.

The compositions of the majority of PSDs contain filaments and occasionally these filaments extend into surrounding cells which also contain particles. The occupancy of the postsynaptic membrane commonly consists of neurotransmitter receptors and ion channels. The filament proteins that make up the structure depending on the localised region i.e. the brain are actin and spectrin. Actin, calmodulin and tubulin play crucial role as structural support. It is considered that the proteins support the rigidity of the binding to postsynaptic density (Siekevits, 1985).

The signaling, scaffolding proteins and the receptors involved for the postsynaptic density organises the transduction signal between the synapse of the postsynaptic membrane. The regulation of adhesion between the postsynaptic and the presynaptic membranes is the function of the postsynaptic density also the control of the postsynaptic receptor and the transmission sent to receptors being activated. (Walikonis et al, 2000)

Chapter 3 Types of mRNA

For many years now it has been established that proteins are synthesised in the soma and transferred to the activated synapse. Evidence gathered to demonstrate proteins can also be synthesised nearby synaptic domains. Proteins that have been encoded by mRNA have regulatory functions (Jiang et al, 2002). The protein synthetic mechanism that has been localised at postsynaptic regions; indicates the possibilities of specific proteins being created can be regulated from the signals of the synapse, thus leading to that mRNA translation is also regulated and controlled by signals of the synapse. By the discovery of the protein synthetic machinery located on synaptic zones on dendrites; development has lead to the identification of dendritic mRNA also giving hindsight that these dendritic proteins synthesised are significant for the continuous synaptic modifications of long-term potentiation (LTP) and also for long-term depression (LTD) (Schuman et al, 2006).

The idea of long-term potentiation is the increased strength also the lasting effects of synaptic transmission sent that can either be short or a continuous pulsation to the excitatory cell fibres the synaptic plasticity. The stimulation of LTP is induced by the activation of N-methyl-D-aspartate receptors (NMDARs) released from glutamate synaptically and affiliated with postsynaptic membrane. Thus reduces the voltage-dependent magnesium inhibition of NMDARs allowing the release of calcium ions flow into the dendritic spines. The calcium ions are essential for the activation of LTP. To get the actual evidence to support that statement experiments had been carried out to ensure the requirement of calcium is necessary by implementing inhibitory experiments.

The suitable applicant for these tests are calcium/calmodulin dependent kinase II (CaMKII) more specifically protein kinase C and the calcium-dependent protease called calpain. By testing hippocampal sections and applying protein kinase inhibitors to protein kinase C and calpain, this prevented the induced effects of LTP. Furthermore direct intracellular injection of protein kinase inhibitor H-7 into CA1 pyramidal cells obstructs the induced effects of LTP. These demonstrated that calmodulin and kinase activity are essential in the postsynaptic zone to produce the LTP effect in the synapse (Malenka et al, 1989).

In the central nervous system (CNS) the synaptic transmission is evaluated by glutamate neurotransmitters and its receptors; whereas in normal transmission in other neuronal cells, the signal is majority of the times mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The N-Methyl-D-aspartate receptors (NMDARs) function only when continuous synaptic action occurs.

This triggers an increased release of calcium ions to pass through NMDAR into the postsynaptic junction; activating biochemical processes related to synaptic plasticity that causes long-term potentiation (LTP). This activation is thought to border between memory patterns in the central nervous system and hippocampus. The concentration of the released calcium ions induces the activation of the enzyme calcium/calmodulin dependent protein kinase II (CaMKII). The NMDAR participates in the regulation of synaptic plasticity and the patterns of memory formation. The phosphorylation of tyrosine from NDMAR regulates the ion channel activity also the localisation of CaMKII in the spines (Manabe, 2008).

Scientists are able to theoretically recreate the possibilities of how translation activity on synapses is synchronized by the processes such as ‘up-regulation’ and ‘down-regulation’ on the actual target mRNA. If there is presence of polyribosomes in the dendritic spines, then it is assumed that one single mRNA strand is being translated at any given time (Schuman et al, 2006). Polyribosomes are a unit of functional proteins synthesised that include many ribosome joined together on a length of a molecule of mRNA (Bramham et al, 2007).

The studies show that there are more than one polyribosomes present in the spines; assuming that more than one mRNA is being translated. That is plausible but unlikely for each individual polyribosome engaged in translation then multiple protein synthesis should occur. Many factors should be taken into account of other proteins present for initiation and phosphorylation, probably not cause the increase amount of translation occurrence; decrease the translation purpose. This raises the question whether having too many polyribosomes present in dendrites affect the alterations of net initiations of the ability of dendrites. There has been evidence suggesting movement of ribosome from the shaft of dendrites to the spines by the signal transmission of LTP; increases the amount of polyribosomes present in synapses. Therefore increase as a whole the ability on translation occurring in a signal synapse. This leaves the theory that idle ribosome not occupied in other translations of mRNA have the ability to move large distances to the source where it is required (Schuman et al, 2006).

The protein NR1 mRNA instructs the makeup of ? subunit of N-methyl-D-aspartate receptor (NMDAR); a receptor vital for the central nervous system neurotransmitter glutamate (Jiang et al, 2002). The named receptor is catogorised in three groups, one mentioned and the other two is ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and metabotropic receptors (mR). The studies of these put forth are different subtypes of these receptors are present on all three groups. The mediation of glutamate receptors exhibit excitatory neurotransmission in the brain also play a very important role in gathering memory functions (Nakanishi, 1992).

CaMKII? mRNA is an ? subunit making the protein calcium/calmodulin dependent protein kinase II (CaMKII) this is an important protein playing its part as inducing activity of LTP and also the phosphorylation of glutamate receptors. The cytoskeleton associated synaptic protein is encoded by activity-regulated cytoskeleton associated protein (ARC) mRNA that maintains the LTP in the brain. The mRNA brain-derived neurotrophic factor (BDNF) is also found in dendrites the receptor for this is TrKB this is activated by BDNF for the first step for the initiation LTP (Jiang et al, 2002).

The localised mRNA that have been identified and what their functions are named on the table below. They are associated with neurotransmitter receptors and regulated by them.

A total of 10 named dendritically localised mRNA have been identified plus the binding proteins associated with the mRNAs. They all have been localised from the dendrites. The functions have been put of those that had gone through extensive research. Taking an example from the table calcium/calmodulin dependent protein kinase II has been dendritically localised from PSD. This protein is involved signaling cascades and in a neuronal perspective it is important for inducing synaptic plasticity. CaMKII once activated encourages the binding protein e.g. fragile X mental retardation protein (FMPR) to develop a synaptic connection to allow communication between the cells. Furthermore the neurotransmitter receptors get phosphorylated by CaMKII changing the way the electrical signals are passed between the synapse. The different neurotransmitters regulate the functions of the binding proteins associated with CaMKII to increase dendritic translation or transport depending which neurotransmitter is in play i.e. NMDA this regulates the translation in the dendrites.

?-Actin & ZBP1

Synapse regulation takes advantage of the ability of actins, to act as a firm component of structural integrity or a dynamic filament. Actins contributes to the effectiveness of presynaptic and postsynaptic sites, furthermore actins do their functional role by various types of actins interplaying in different signaling pathways (Cingolani et al, 2008). In order for ?-actin to be localised a binding protein called Zip-code binding protein 1 (ZBP1) is required for ?-actin to be localised in dendrites. So ZBP1 and ?-actin are colocalised in dendrites and spines (Eom et al, 2003). They way in which dendrites branch out, at the same time the synaptic density as well as the arrangement of the receptors on the membrane, characterises the properties of the electrical signal in the neuron. The growth of dendritic arbors and the way they are strengthened are precisely coordinated in molecular perspectives that are guided by essential mechanisms. ZBP1 manages the way in which ?-actin is transported and translated in the dendrites. ZBP1 are vital in the development of dendritic arbor in neurons. This suggests that ZBP1-dependent dendritic mRNA for transport is a factor for appropriate dendritic branching (Perycz et al, 20011).

ARC

Activity-regulated cytoskeleton-associated protein (Arc) is part of the immediate-early gene (IEG) family that can be activated very quickly when required. They have the ability to be translated in the presence of inhibitors of protein synthesis. Arc mRNA has been localised in the synapse that has been activated synaptic activity in the presence of N-Methyl-D-aspartate (NMDA) receptors. Arc functionality is the active role in regulation, the point of localisation and used as marker to observe changes in plasticity. Long-term potentiation (LTP) is supposed to show relationship to learning and memory. Continuous forms of LTP and protein synthesis changes the structure and constitution of proteins at the synapses. Signals from the synapse to the nucleus in the cell body of the neuron triggers gene expression; producing proteins that can change constitution of protein networks, thus providing a mechanism translating synaptic activity to make changes to the synaptic strength. Arc has activity regulated properties that makes it fundamentally exceptional when it is initiated by LTP stimulation and sent to dendrites, and within the dendrites Arc can be pin pointed to the activated synapse. This indicates that it is translated on site assuming that it is transported in a dormant state and translated in the synapse in contact with NDMA receptor and also mitogen-activated/extracellular-regulated protein kinase (MAPK/ERK) (Plath et al, 2006).

CaMKIIa

Calcium/calmodulin-dependent protein kinase II (CaMKII) is part of the serine/threosin-specific kinases. They are regulated by calcium/calmodulin complexes and engrossed in different types of signaling cascades. It has a tendency for autophosphorylation, meaning the phosphorylation of a kinase protein catalysed by its own enzymatic activity. It can continue its activity even after the extracellular calcium ions are depleted which is needed for its initial activation. When it is activated, it phosphorylates glutamate receptors in the postsynaptic membrane that causes alteration to the electrical transduction on the synapse. This is important in neurons more specifically the synaptic plasticity. Calcium ions play a critical signaling indicator in the form such as activity dependent synaptic plasticity. It has been observed that calcium ions can take control in replacing used vesicles after a synaptic depression when the signals have been passed through and deactivated. Further observation has shown calcium ion in dendritic spines encode in a precisely timely manner of presynaptic input and postsynaptic action and produce a lasting effect for synaptic alterations (Zucker, 1999).

It has been known that CaMKII is essential for LTP induction and constantly activated by the stimulation of the LTP that had been induced and fine tune the synaptic transmission. It has been indicated that CaMKII can be used as a switch proficient of long term memory accumulation for its ability of autophosphorylation and dephosphorylation (Lisman et al, 2002).

CaMKII located in dendritic spines is controlled by associated factors, mentioning the capability to bind calcium/calmodulin, state of phosphorylation and the synthesis of newly created subunits in dendrites. It has been acknowledged that the location CaMKII is absolutely imperative for the form and survival of synaptic plasticity. What is also known about CaMKII can move into and out of the postsynaptic density (Fox, 2003). CaMKII regulates the excitatory transmission in the synapse; this has been known for nearly 20 years and is the postsynaptic density protein. These findings lead to mechanisms that are tuned to be more or less flawless for the size and location of CaMKII activity (Colbran et al, 2004).

eEF1A

In the elongation phase where amino acids are added to the growing peptide chain as the ribosome translocates a single codon to the matching mRNA. The regulation of elongation is not difficult or complex but still different from initiation. Strong evidence from neurons suggests that eukaryotic system is able to manage translation by modulation. This is very important for cellular functions. Two elongation factors are responsible for the engagement of new aminoacyl-tRNA to the alpha site of the ribosome. The two factors are eEF1A and eEF1B that get phosphorylated by calcium ion-dependent PKC (protein kinase C) isoforms showing that they increase elongation activity. The elongation factor eEF2 is the third type of elongation factor. This needed for translocation of ribosomes along the mRNA strand. The phosphorylation of eEF2 inhibits its binding ability to ribosomes; eEF2 kinase (eEF2K) shows its dedication solely to the regulation to eEF2; eEF2K is a calcium/calmodulin dependent protein kinase and in neurons during phosphorylation is regulated in manner of activity dependent (Sutton et al, 2005).

FMR1 & Fragile X Syndrome

FMR1 (fragile X mental retardation 1) is a gene found in humans that codes for fragile X mental retardation protein (FMRP) this produced in different tissues, in relation to dendrites in the brain. This protein FMPR can act as inhibitor in translation in dendrites. Its role is thought to be in the development of synaptic terminals to allow cell to cell communication. The junctions between nerve cells can alter and adapt over a period of time to the response of electrical transduction whereby signals are passed through the pre and postsynaptic zones, these are called synaptic plasticity (Vanderklish et al, 2005). If by chance a transcriptional silencing to occur on the FMR1 gene, will lead to a genetic disorder called fragile X syndrome. The gene does not synthesise the FMPR protein because it has been switched off, the FMR1 protein is translation-dependent. FMPR is a binding protein that is expressed in humans and mice tissues, predominantly in the brain for its high expression in neurons, where the localisation occurs in the cell body and in a granule along the dendrites. FMPR regulates trafficking on halted mRNA complexes and manipulates protein synthesis in synapses (Khandjian et al, 2004).

GluR1 & GluR2

GluR1 and GluR2 are subunits of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). They mediate the high speed transmission of the synapse in the CNS. It is an analog of AMPA which it can be activated from (Passafaro et al, 2003). GluR2 role is considered to increase spine size and density. It though that it’s N-terminal domain (NTD) is responsible for its functions on the cell surface as a part of a receptor-ligand interaction (Inglis et al, 2002). GluR1 functions for controlling dendritic growth where it binds to SAP97 protein which is a scaffolding protein, a component for postsynaptic density (Zhou et al, 2008).

InsP3R

Inositol triphosphate receptor (InsP3R) is a ligand-gated channel that allows the release of calcium ions from storage organelles. It has been established that the changes to calcium ions from the InsP3 receptors put coordinated rhythmic functions at very high risk. InsP3R act as a second messenger also it interacts with other different signaling pathways that regulate the cytosolic calcium ions that can directly activate other signaling pathways involving calmodulin and protein kinases. So by these interactions suggests that by maintenance of calcium ions can be regulated by the activity of InsP3R (Banerjee et al, 2005).

LIMK1

Lim-domain kinase 1 is an enzymatic protein encoded by LIMK1 gene in humans. The LIM domains are very highly cystein-rich structures that contain two zinc fingers. This protein promotes the interaction for a protein-protein association. LIMK1 is thought to be part an intracellular signaling pathway. This regulates the actin filaments by the inhibition of ADF/cofilins (ACs) which are groups of actin–binding proteins that sever and disassemble actin filaments. LIMK1 is responsible for the function and formation in the synapse. The mechanisms for the formation of spines how they become stable and set up in dendrites are still unknown. The appearance of dendritic spines is thought to be affected by LTP and get affected by it too, that in turn controlled b alteration in the actin filament structure. Actin filaments are actively part of the regulation of receptor complexes also formation of working synapses. So by the disruption of actin filament in neurons causes severe problems for learning, memory and the development (Sarmierea et al, 2002).

tPA

Tissue plasminogen activator (tPA) which is encoded by the PLAT gene goes through the process of alternative splicing. It has many cellular functions that are important such as learning-related synaptic plasticity and the effectiveness of NMDA receptors-dependent signaling. The data shows release of tPA on site assists for the interaction with NMDA-type glutamate receptor (Lochner et al, 2006). The protein tPA synthesis occurs in the synaptodendritic site, the increase of this protein is dependent on mGluR activation also what was found tPA is bound to an mRNA-binding protein CPEB1 (Shin et al, 2004).

Dendrin

The occurrence synaptic plasticity and memory formation is the requirement of the postsynaptic cytoskeleton to be restructured and altered. This is partly involved of dendritic mRNA and the recruitment of newly synthesised proteins from the synapse. Dendrin is encoded by dendritically localised mRNA that adapts and alters the structure of the synaptic cytoskeleton. The results of Dendrin being studied shows that it interacts with the components of cytoskeletons of alpha-actinin (?-actinin) and synaptic scaffolding molecules (S-SCAM) making dendrins reliant on scaffolding molecules and local protein synthesis (Kremerskothen et al, 2006).

Staufen

This is a double stranded RNA binding protein that is a major component of different RNA granules; plays an important procedure during the transport of dendritic mRNA. Staufen mediates dendritic mRNA and in turn is regulated by neuronal activity (Kim et al, 2006).

BC1

Brain-specific cytoplasmic 1 (BC1); synthesis of proteins in dendrites is relatively triggered by different paradigms that can be such induced effect resembling seizures or epilepsy. By these influences acted on BC1 is a translation repressor that undergoes modulation by the affects of stimulation (Nimmrich et al, 2005). BC1 tends to be subject of is activity-dependent modulation. BC1 is a part of specific repressor for starting translation; cap dependent and the modes of internal entry. Its function role is the control of gene expression in neuronal cells (Wang et al, 2002).

MAP2

Microtubule-associated protein 2 (MAP2) a protein encoded by a MAP2 gene in humans. It relates to growth factors, neurotransmitters, synaptic activity and neurotoxin (Johnson et al, 1992). Involved in assembling microtubules which really important for the growth of neuron cells. They stablise microtubule growth and cross linking with other intermediate filaments, classed as neuron-specific cytoskeleton protein which is full in dendrites. The mechanisms of MAP2 are the control of neuronal cytoskeleton that is modified by the phosphorylation state of the cytoskeletal proteins due to the alteration of active protein kinases and phosphatases. MAP2 is thought to regulate the transport of organelles within dendrites and axons. It plays part in neuronal cell death, synaptic plasticity and growth of neurons outwards (Sanchez et al, 2000).

Chapter 4 Transport & Mechanism of mRNA to target Dendrites

Typically neurons possess an exceptionally polarised cell structure. Furthermore a long thin filamentous axon that has many dendritic appendages emanating from the neuronal cell body. Characteristically the dendrites differentiate from one another from how they look and appear also their functionality. The intracellular signaling pathway cascades and trafficking pathways varies from the dendrites to the axon. What is fundamentally known is that specific proteins that is designated for the axon towards the presynaptic junction; synthesised within the cell body then transported in protein complexes to its destination. The destination of the proteins is the dendrites/ dendritic spines towards the postsynaptic terminal; passed on from the cell body another detachment of mRNA are transported to the dendrites to further assist in the synthesis of local proteins. The focus on motor proteins that act as a go between for RNAs that have been demanded for their destinations either the axon or the dendrites with association of RNA-transporting granules. Within the structures of the dendrites and axon there are long length of ‘tracks’ that run along the length on most of the dendrites and axons.

These are called microtubules their purpose is to assist in transporting membranous organelles and complexes of macromolecules. The polarity of microtubules are unipolar especially those that are from distal dendrites and axon. In comparison to those microtubules located in proximal dendrites generally have a mixed polarity. The molecular motors that move by sliding along the microtubules are called kinesin and dynein that haul different types of loads and these motors are both dependent on microtubules. The molecular motor kinesin is part of the kinesin superfamily protein (KIFs), characteristically they travel towards the plus (+) end terminus of the microtubule which is known as anterograde transport (Hirokawa, 2006).

The KIFs play a very important role in the process of intracellular transport, which is also vital for the cellular function as well as its morphology. They are recalled as the first large protein family identified in mammals in sillico and in vivo (Mikia et al, 2005). A further study into the kinesin superfamily proteins has lead to understanding of their mechanisms. How different kinesin are able to recognise and be specific in their binding to specific loads also the way they unload their cargo they are transporting and the ability to determine in which direction to travel. It had been evident by carrying out molecular genetic experiments lead to the unearthing of the kinesins other roles such as higher brain functional role in regulation, suppression of tumors (Hirokawa et al, 2009).

The other molecular motor protein called dyneins do the opposite of kinesins. They travel towards the minus (-) end terminals of the microtubule that is known as retrograde transporting their loads from axonal or dendritic locations towards the cell body (Hirokawa, 2006). During the finding of cytoplasmic dynein it has been obvious that dynein which is microtubule dependent motor that is engaged in transport functions as well as cell division. Investigations have led to the finding of another multi subunit complex called dynactin, which is also required if not completely necessary for all cytoplasmic dynein related activity (Karki et al, 1999).

It is well known that the distribution of mRNA can be found in dendrites also in neuronal axons. Moreover the method by where particular mRNAs are transported is still unknown or unidentified. What is known though the complexity of neuronal dendrites and the processes of mRNA localisation include the requirement of many mRNA binding proteins. However there are also another three more types of RNA- containing granules. The three types are ribonucleoprotein particles (RNPs); mRNA that include transport granules, motor proteins, mRNA binding proteins and microRNA they are non-coding RNA. Stress granule (SGs) which is a protein fluid type substance from cytosol with a mixture of RNA that manifests during cells undergoing pressure or strain. The mentioned RNA molecule is thought to halt the pre-initiation complex of translation. Processing bodies (PBs) structures related to the cytoplasm where it is assumed that mRNA degradation occurs on it site. The facts based on the molecular efforts for mRNA transport and translation in neurons was actually assumed from the processes carried out in non-neuronal cells.

The next assumption was that majority of mRNAs are transported within dendrites that have been packed into large RNPs which are in transported in dormant state. For specific mRNAs to be targeted dendritically they first must be separated or isolated individually from the translation mechanism in the cytoplasm. Then they have to be packed and organised into these RNPs. Usually the separation occurs in the nucleus. The mRNA has its binding proteins remained attached to it as it is transported from the nucleus to the dendrites. An initiation factor protein for eukaryotic cells called 4AIII (eIF4AIII) this is responsible for the involvement of pre-mRNA splicing within the nucleus. This protein is also related to two dendritic mRNA that codes for the protein called fragile-X mental retardation protein (FMRP) and activity-regulated cytoskeleton-associated protein (Arc).

The eIF4III protein is thought to be taken away from the mRNA by reading the transcript by the association of the first ribosome it comes contact with; indicates that mRNA from dendritic sites have not been translated before. However the molecular mechanisms engaged with mRNA sequestration and transport to dendrites are still unknown, extensive studies have been carried out for the regulation of mRNA ?-actin with use of RNA-binding protein, zip-code binding protein 1 (ZBP1). This is an indication implying that not all RNA-containing granules are made up in the same arrangement; furthermore there are two other RNA-containing granules also in the dendrites they are SGs and PBs the relationship between the RNPs are still not verified (Bramham et al, 2007).

The contribution towards synaptic plasticity is thought to be contributed by the localisation of mRNA to synaptic zones and later followed by the local translation. Many RNAs have been distinguished and catogorised those include Arc, non coding RNA brain specific cytoplasmic 1 (BC1), MAP2 and CaMKII?. The mechanisms of these RNA in primary neurons are still not fully understood. To solve the problem are these RNA-binding proteins (RBPs) more specifically Staufen proteins, zip-code binding proteins (ZBP), fragile X mental retardation protein (FMRP). They all have been implicated with localised dendritic RNA. Furthermore being tagged with fluorescent variants to see if they are directly or indirectly associated with RNPs and dendritic transcript on how they move along the dendrite either as a complex or not. There is no further evidence to suggest that the interaction is either established and/or exclusive. Many techniques have been implemented to visually see localised RNA. Many scientists assessed RNA by in situ hybridisation (ISH) in cultured or disassociated neurons and a much recent form microinjection of fluorescently labeled RNA to live neuron sample to visualise in real-time images of individual dendritic RNAs. These methods are mainly used to study the molecular mechanisms of dendritically localised RNA. It still remains unclear as to whether different RNA is targeted to dendrites by independent pathway or a trafficking pathway (Tubing et al, 2010).

Particular mRNAs end up being localised in dendrites and most of the times they are clustered together in dendritic spines to be translated. The mechanism of localisation is yet to be determined by observing closely on the roles of A2 response element (A2RE) this is a cis-acting signal for oligodendrocyte in RNA trafficking (Shan et al, 2003). An oligodendrocyte function is to myelinate axons i.e. myelin sheath cover the length of the axon that allow rapid electrical impulses to pass through. This is to increase the axon stability and strength to encourage build up and phosphorylation of neurofilaments in the axon (Wilkins et al, 2003). They remyelinate to re-establish saltatory conduction that allow the hopping effect of action potentials from one myelin sheath section to the node of ranvier to the next myelin sheath of the axon. This brings about the axons to normal function after it was lost during the period of demyelination (Keirstead et al, 1999).

In regards to A2RE and to its counterpart heterogeneous nuclear ribonucleoprotein (hnRNP) a trans-acting factor, by injecting fluorescently labeled chimiric RNA of A2RE in hippocampal neurons showed transport of RNA including those containing granules to distal neurites. Neurites are undifferentiated protrusions that can either be of dendrite or axon origin due to immaturity of cultured neuronal cells. A2RE can be inhibited in the RNA transport if an antisense ogligonucleotide is present on neurons furthermore by adding colchicine blocked trafficking; Colchicine function is to target microtubules and inhibit polymerisation by directly binding to tubulin which is the main component of microtubule growth. By treating neuronal cells with cytochalasin did not affect it in any way. This suggested that the involvement of microtubules is important and actin filaments are not hence the adding of cytochalasin that inhibits actin polymerisation. This suggested the idea that cis-acting sequences contributed to the localisation of dendritic RNA (Shan et al, 2003).

The acceptance of mRNA move to dendrites where translation occurs is regulated by the response of neuronal activity and studies into this highlight the importance of protein synthesis, the remodeling of synapse to the synaptic plasticity. Studies carried out by Steward et al, (1982) shed light onto which individual synapses could work independently; regulate morphology and effectiveness in a continuous manner during protein synthesis whereby responding to a specific stimuli. The mechanism described is the way translation in localised mRNA is regulated that allows certain proteins to be synthesised. The main aspect of this feature is that mRNA that have been localised requires a pause or break of activity until a specific signal is sent to say which mRNA needs translating first etc. This mechanism is further assisted by internal ribosomal entry sites (IRES). These are needed to be present during the initiation of translation. These IRES are like microRNA (miRNA) they act as the regulator that allows the translation to occur or to halt the process until a specific signal of demand is instigated.

They have been found to be located around synapse, studies of these miRNA showed their trait by being generated continuously was necessary to hold back translation. Other studies of miRNA showed the binding of mir134 onto 3’ untranslated region of an mRNA that encoded for the protein called Lim-domain Kinase 1 (LIMK1) and the concentration of mir134 also altered the concentration of LIMK1 and by the alteration of this concentration changed the structure of the spines. These findings were reliable with miRNA functions due to that it regulates translation in synaptic zones furthermore these regulations are also needed for development of normal spines (Martin et al, 2006).

In the formation of a synapse that involves the release of neurotransmitters in the presynaptic site to an accessible zone on the postsynaptic zone were both are aligned. Precision is required for presynaptic and postsynaptic areas to come together to form a synapse at same time the postsynaptic density. This indicates that neurons have the ability to grow to maturity in respond to many different types of stimulus. In the processes for both occurrence protein synthesis is needed. More specifically translation in the local dendrites; specific mRNA in close proximity to dendritic spines are able to be translated within various spaced of the dendritic spine. The paces as to how translation occurs are regulated by other agents that stimulate translation or inhibit the translation. These points out different signaling pathways adjust and adapt localised protein synthesis (Glanzer et al, 2003).

The regulation for growth cones on dendrites remain uncharted however it is thought that mRNA localisation and the proteins synthesised in dendritic growth cones are important to the growth cone functions. Tests had been carried out that show protein synthesis in dendrites as well as growth cones from hippocampal neurons showed trends of regulation that varies the cone structure. This suggests that mRNAs that have been translated may play a role in the regulation of growth cones and the way the dendrites grow outwards. Growth cones occur from the far ends of dendrites and axons. They direct dendrites and axons towards the desired target of expansion. It is known that proteins have to be transported to dendrites that are essential for growth cones to occur. Those proteins that have been identified from mRNAs are microtubule associated protein 2 (MAP2), ? subunit of calcium/calmodulin dependent protein kinase II (CaMKII?), brain derived neurotrophic factor (BDNF), activity-regulated cytoskeleton associated protein (Arc) also many other types of glutamate receptors. By these proteins being synthesised suggested that further proteins are produced by the named proteins above for dendritic functions. The localised mRNA undergo translation on the tips of dendrites that allow the dendrite outgrowth to occur from these outgrowth samples had been taken and analysed showed some proteins present in the growth cones but all indicated not all proteins that are found locally in dendrites are present suggesting even in the new growth cones regulation of allowing specific protein synthesis to occur (Crino et al, 1996).

Chapter 5 Discussion

Many mRNA have been dendritically localised dating as far back from 1985 to the present day where they still are extensively researched and continuously experiment in different forms of analysis. There are still many unidentified transcripts that have not been studied and the proteins that they synthesise. The findings up until now is that mRNA are localised to dendrites but before that it was said that proteins were synthesised in the cell body then transported to the dendrites. The evidence put forward for mRNA can be localised in dendrites was first proposed by steward (1994) that dendrites can be utillised as a section for synthesising proteins. His assumption was based upon the presence of ribosomes present in dendrites; essentially ribosomes play a role in translating mRNA in to newly synthesised proteins. To answer the raised questions was difficult at the time due to the limited techniques available also the way his experiments were implemented using glutamate receptors.

Moving six years ahead you come to a period where neurotransmitters have been researched extensively as well the localising mRNA from dendrites. The research on the dendrites indicate that proteins are definitely synthesised in dendrites by a regulatory mechanism, which leads to the research of neurotransmitters where by glutamate receptors regulate the different synthesis of different proteins in dendrites. In turn the synthesis of these proteins that had been identified led to the identities of their functions in relation to the synapse. The identities of dendritic mRNA led to the specific functions of respective proteins. The isolation of these proteins showed that they are established in many different functional roles relating to receptors, ion channels, cytoskeletons, signal inductions, translation factors, RNA-interacting proteins, ribosomal proteins, protein transport, membrane trafficking, growth factors and molecular motors. In short dendritic mRNA that had been implemented on showed the location of the translation, the transport of mRNA to dendrites and the functions of the synthesised proteins. The transport of mRNA to dendrites had been studied, indicating that they are transported from the cell body to the dendrites via microtubules on motor proteins. The findings relating to transport is that mRNA are being transported in protein complexes to its destination. These protein complexes involved are RNA-binding proteins that ensure that mRNA is in a dormant state during transport. Upon synaptic activation the required protein is synthesised.

There had been a few references that coincide with the localisation of dendritic mRNA associated with diseases. Those diseases that have been associated are Fragile X syndrome, Alzheimer’s disease and Huntington’s disease. Fragile X syndrome (FXS) is inherited diseases were synthesis of FMRP is silenced during gene expression that is encoded by FMRP1 gene. This switches off the process that allows the synthesis of this protein. It plays a general role in dendrites with inhibitory purpose, development of synaptic terminals for communication between cells. It also regulates the trafficking inhibited mRNA complexes. The latest regards to this disease had shed some light on the way to tackle it by therapeutic means is described by Gross et al, (2010) the method to treating FXS is by signaling through group 1 metabotropic glutamate receptors (gp1 mGluR). Indication of this disease showed the dysregulation of different receptor-mediated signal transmission pathways. FMPR deficiency led to high amount of active phosphoinositide 3-kinase (PI3K), which is associated with signaling molecules of a variety of cell surface receptors. Test result show inhibiting gp1 mGluR increases further of PI3K which increased internal AMPARs and increase of spine density. By targeting the high amounts of PI3K activity can be a way forward for therapeutic methods for FXS.

The association with Alzheimer’s disease is a neurodegenerative disorder that occurs due to the loss or alterations to dendritic spines. The remodeling and formation of new synapse are related to the basis of memory formation. This alteration and loss of dendritic spines is stimulated by amyloid ? (A?) that is a plaque forming on the brain of people who suffer from Alzheimer’s disease (Knobloch et al, 2008). In relation to Huntington disease with dendritic mRNA is described by Savas et al, (2010) the studies indicated that RNA granules in neurons share a commonality in structures and functions of processing bodies (PBs). The PBs were first mentioned by coincidence by Bashkirov et al, (1997) describing them as small discrete granules. It was not until 2002 that it became widely accepted as processing bodies. In regards to Huntington disease a protein called huntingtin (Htt) is produced with people that lead to neurodegenerative disease that affects muscle coordination and in time to cognitive declination. The protein Htt associates with Argonaute (Ago) which localises to PBs in the cytoplasm. They function as mRNA storage, small mRNA –mediated gene silencing. In association with Ago2 suggest that Htt co-localised with neuronal granules and the results indicated Htt function is to repress translation of mRNA s when they are being transported in neuronal granules.

The latest findings and development of localised mRNA in dendrites for the last three years had shed more light into this particular field of investigations. Taking the work described by Bramham, (2008) he worked on Arc and relation to BDNF where this protein signaling pathway activates Arc-dependent LTP consolidation which is essential for actin polymerisation and the firm increase of dendritic spines during the effects of LTP. The regulations of different types of actin pools in dendritic spines modulating the spine size, the way the postsynaptic density is organised under the postsynaptic membrane. The receptors involved in trafficking and the compartment of the protein synthesis mechanism in the dendrite.

There has be new insight in the last two years in regards to BDNF that had been referred by Waterhouse et al, (2009) and Greenberg et al, (2009) they both mention that BDNF is important for synaptic plasticity. Studies show that protein synthesis has been identified locally and is important for the new protein in the period expression enduring synaptic plasticity. This relates to the understanding of the mechanisms involved in restricting the action of BDNF towards active synapses. In activation BDNF acts an intermediate for chemical and structural alterations for individual synapses. What also had been enlightened with BDNF has pleiotropic effects on the development of neurons as well as the plasticity to circuit formation and cognitive function. Pleiotropic is referred to a single gene that causes multiple effects.

The studies into microRNA (miRNA) have shown little or limited amount of data suggesting their functions and key roles in dendrites during translation of mRNA. The findings recently observed by Schratt, (2010) explain that there are at three types of miRNAs involved for changes, appearance of dendritic spines also mentioning the specialised structures in dendrites of synaptic contact. The miRNAs mediate regulation of protein synthesis in turn influences the essential modulation of actin cytoskeleton within dendritic spines. It can play a very important role for the maintenance of cellular and network homeostasis.

A new finding of the Apolipoprotein E (APOE) investigated by Oh et al, (2010) is transported to dendrites and considered to be relevant for lipid rafts and/or synaptic plasticity. Research into dendrites of a squid showed the extraction of a 65kb protein that positively bound to a monoclonal antibody and further tests revealed that it was part the heterogeneous nuclear ribonucleoprotein (hnRNP). Zhong et al, (2010) experimented on animal models to see the outcome if both proteins BC1 and FMR1. The results concluded that the two proteins play a similar role as translation repressors. What would be the effects if both of them proteins was to be double ‘knock out’, it showed that the animal was totally impaired compared to individual single ‘knock out’. This led to the fact because both play roles in translational repressors and they both work in sequential- independent manner, they both have critical impact in the brain functions.

The study of CaMKII? by Bingol et al, (2010) shows the interaction of proteasomes this only occurs when CaMKII is in autophosphorylated state in the brain, where the CaMKII? protein acts as a scaffolding protein binding proteasomes to it by recruitment to the dendritic spines. The translocation of CaMKII? to postsynaptic density is biochemically associated to proteasomes that acts as protein degradation when CaMKII? phosphorylates proteasomes making it degrade polyubiquitinated protein in the dendritic spines.

Chapter 6 Conclusion

It has been established many times that dendritic mRNA that had been critically analysed.

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