Postsynaptic+mechanisms+of+synaptic+plasticity

= under Neurophysiology of Learning and Memory =

 Discovering the mechanism underlying learning in the brain is a fundamental aspect of understanding how the brain works. Learning involves neuroplasticity, the ability of the nervous system to change structurally and functionally. This plasticity is fundamental for behaviours such as addiction (i.e. alcohol addiction, sex addiction, food addiction) (Hyman, 2006) and social interactions (Yang, 2012) while impairment to plasticity from factors like neurodegenerative disorders (i.e. Huntington's Disease) (Zeef, 2012) disrupts cognitive abilities like learning and memory (Lacor, 2007; Ondrejcak, 2010; Zeef, 2012). An important component of neuroplasticity involves the strengthening or weakening of the [|synapses].

Synapses, which can be considered the basic functional unit of the nervous system, can be altered through activity-dependent processes such as long-term potentiation (LTP), which causes long-lasting strengthening of synaptic response, and long-term depression (LTD), which causes long-lasting weakening of synaptic response (Bi, 1998). A significant amount of experimental results came from post-synaptic research. Specifically, post-synaptic receptor activation (Bi, 1998), calcium driven mechanisms (Ghosh, 1995), dendritic spine properties, and cytoskeletal changes (Luscher, 2000; Hussain, 2001; Irie, 2002; Star, 2002; Carlisle, 2005; Rex, 2007; Bennett, 2011) have been shown to be related post-synaptic plasticity and learning.


 * ===**Table of Contents **===


 * Activation
 * Calcium Dependent Pathways
 * CaM Kinases
 * Adenylyl Cyclase
 * AMPA Receptor
 * Cytoskeletal and Spine Changes
 * Filopodial Protrusion
 * Actin-Related Processes
 * Rac - PAK - LIM Kinase Pathway
 * Intersectin-cdc42-N-Wasp-ARP2/3 pathway
 * NMDAR-dependent Pathways (gelsolin and profilin)
 * Disruption by ADDLs
 * References ||


 * 1 Activation **

Two kinds of excitatory receptors involved in plasticity that have undergone extensive research are N-methy-D-aspartate receptors (NM DAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) (Mayer, 2004). AMPAR requires glutamate binding to activate, allowing Na<span style="font-family: Arial,Helvetica,sans-serif; font-size: 8px; vertical-align: super;">+ flow into the neuron and causing an excitatory postsynaptic [|potential]. NMDAR requires both ligand and voltage activation, where depolarization of the cell removes an extracellular magnesium ion block while glutamate binds to the receptor, inducing conformational change, allowing both [|Na] <span style="font-family: Arial,Helvetica,sans-serif; font-size: 8px; vertical-align: super;">[|+] <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;"><span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;"> and [|Ca]<span style="font-family: Arial,Helvetica,sans-serif; font-size: 8px; vertical-align: super;">[|2+] to enter (Ghosh, 1995).

Video 1: NMDAR Activation (Animation by Pete Bilderback). NMDAR is both ligand and voltage gated. The voltage change in the video is shown by the change in membrane colour. ||
 * = media type="custom" key="13703602" width="250" height="250"

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">While both receptors lead to depolarization, NMDAR also brings about intracellular calcium ion concentration changes. Cytosolic calcium ion concentrations are very important in calcium dependent second messengers and pathways, which are involved in plasticity.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">2 Calcium Dependent Pathways **

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Increased cytosolic Ca<span style="font-family: Arial,Helvetica,sans-serif; font-size: 9px; vertical-align: super;">2+, from extracellular sources or internal calcium stores, can lead to several second messenger related cellular responses. Pathways leading to increased calcium include NMDAR activation, which affects concentrations both directly and indirectly through depolarization and opening of voltage-gated Ca <span style="font-family: Arial,Helvetica,sans-serif; font-size: 8px; vertical-align: super;">2+ <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;"> channels and cytosolic-calcium-mediated calcium stores in the endoplasmic reticulum (Ghosh, 1995). Calcium stores may also be opened by the binding of inositol triphosphate (IP3), which in turn can be generated from GTP-linked receptors (Kaplin, 1994). <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Ca<span style="font-family: Arial,Helvetica,sans-serif; font-size: 8px; vertical-align: super;">2+ binds to the protein calmodulin inside the cell. The complex, calcium-calmodulin (CaM), then can bind to a variety of other cellular components such as CaM-dependent protein kinases (CaMK) and adenylate cyclases, altering their activity (Lisman, 2002). <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">CaMK is an important enzyme for phosphorylating and activating various signaling pathways. CaMKII and CaMKIV in particular have been shown to be localized in the nucleus and activate wide-acting proteins such as MAPK and cAMP response element-binding protein (CREB) (Bozon, 2003). These proteins in turn increase various plasticity related gene expressions, such as BDNF (Sun, 1994; Tao, 1998; Bramham, 2005; Rex, 2007), zif268 (Bozon, 2003), and PKMzeta (Hernandez, 2003). <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Moreover, CaMK has been shown to be able to autophosphorylate, remaining active even when intracellular Ca <span style="font-family: Arial,Helvetica,sans-serif; font-size: 8px; vertical-align: super;">2+ <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">levels have returned to normal (Ghosh, 1995). This powerful mechanism makes it a very important protein in postsynaptic plasticity. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Another target of CaM is CaM-dependent adenylate cyclases. Adenylate cyclases can influence cAMP levels, which in turn has been shown to be related to memory in animal models, such as rodents, //Drosophila// and //Aplysia// (Ghosh, 1995). <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">NMDAR activation have been shown to induce LTP and LTD through the exocytosis and endocytosis of AMPAR. With the activation of CaMKII and calcium-dependent Ras-ERK pathway, AMPAR carrying vesicles fuse with the membrane during LTP (Patterson, 2010; Lisman, 2012). However, the localization of exocytosed AMPAR to the spine head requires the likely CaMKII-dependent phosphorylation of [|stargazin], a member of the TARP family (Tomita, 2005). Stargazin interacts with scaffold protein [|PSD-95] to help trap and localize AMPAR at postsynaptic sites (Bats, 2007). <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Membrane-bound AMPAR become endocytosed during LTD (Malinow, 2002; Bredt, 2003), where LTP is characterized by an increase in synaptic strength from a high number of NMDAR activation due to high frequency stimulation and LTD is characterized by a weakening of synaptic strength due to low frequency stimulation.
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">2.a CaM Kinases **
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">2.b Adenylyl Cyclase **
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">2.c AMPA Receptor **

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">It makes sense that an increase of AMPAR density at the synapse is associated with LTP as more receptors can contribute to the excitatory postsynaptic potential on subsequent stimulations. Likewise, a decrease in AMPAR density would mean a weaker postsynaptic potential.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">In addition, GluR1, a subunit of AMPAR, can be phosphorylated by PKC or CaMKII at specific sites (i.e. S831), which have been observed to increase conductance of AMPAR through conformational changes (Kristensen, 2011). However, increase in conductance due to GluR1 phosphorylation requires stargazin (Kristensen, 2011; Lisman 2012).


 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">[[image:ampar.jpg width="480" height="303"]]

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Figure 2. CaMKII Dependent Modifications of Postsynaptic AMPAR properties in LTP (Lisman, 2012) || media type="youtube" key="GadTwDXAYUQ" height="322" width="421" Video 2: Insertion of AMPAR with Fluorescent Microscopy (Yudowski, 2007). ||


 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px; vertical-align: middle;">3 Cytoskeletal and Spine Changes **

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Plasticity has been associated with morphological changes. Cytoskeletal changes are known to occur, such as growth of new and existing dendrites and splitting of existing synapses (Malenka, 2004) and they provide better, more effective synaptic connections. The high concentrations of actin in the spines are subject to polymerization and depolymerization through various pathways, leading to a highly dynamic cytoskeletal structure (Carlisle, 2005) that affects the synaptic connections of the postsynaptic neuron.  <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Filopodial protrusions are important during development as they extend and retract based on exposure to neurotransmitters to later form dendritic spines as protruding filopodia come into contact with growth cones (Carlisle, 2005). Studies of blockage of NMDAR seem to suggest filopodial growth depends on cytosolic Ca <span style="font-family: Arial,Helvetica,sans-serif; font-size: 8px; vertical-align: super;">2+ <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;"> (Luscher, 2000). LTP-inducing stimuli have also shown rapid filopodia extensions in mature neurons (Carlisle, 2005).  <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">[|Fluorescence resonance energy transfer](FRET) based techniques have shown high frequency titanic stimulation as typically used for LTP leads to polymerization of actin filaments in spines whereas low frequency stimulations as typically used for LTD leads to actin depolymerization (Carlisle, 2005). This supports the idea of creating new or altering existing spines.  <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Recent hippocampal studies have suggested that actin dynamics in spines involves the Rac-PAK-LIMK-Cofilin pathway. There are multiple messengers that result in this same pathway; two well-studied pathways will be presented. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">One pathway starts by activation of EphB receptors located on spines by physical contact with axonal membrane-bound ephrins. EphB then activatves Rho GEF kalirin, which in turn activates Rac. Rac is a part of the Rho family GTPase, known for their regulation of actin cytoskeleton in spines. Specifically, Rac activates p21-activated kinases (PAK), which activates LIM kinase 1 (LIMK1). LIMK1 deactivates, through phosphorylation, cofilin, which reduces depolymerization of actin filaments. As actin filaments are constantly undergoing both polymerization and depolymerization, reducing depolymerization enhances the polymerization effect, leading to rapid growth of the dendritic spine (Carlisle, 2005).
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">3.a Filopodial Protrusion **
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px; vertical-align: middle;">3.b Actin-Related Processes **
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px; vertical-align: middle;">3.b.a Rac - PAK - LIM Kinase Pathway **

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">Another pathway that uses the Rac-PAK-LIMK-Cofilin pathway involves NMDAR. As NMDAR is activated, cytosolic Ca2+ is increased, CaM is generated, leading to activation of β CaMK Kinase (CaMKKβ) and CaMKI. CaMKKβ and CaMKI in turn phosphorylates Ser516 in βPI<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">X, which interacts with Rac, turning on the Rac-PAK-LIMK pathway as described above (Saneyoshi, 2008). 

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">**3.b.b Intersectin-cdc42-N-Wasp-ARP2/3 pathway** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">EphB receptors have also been shown to interact and accumulate intersectin-1 in the spine. The accumulated intersectin recruits N-Wasp, which enhances intersectin’s GEF activity. This allows intersectin to activate Cdc42, which causes actin polymerization through N-WASP and ARP2/3 (Hussain, 2001; Irie, 2003). <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">NMDAR activation causes an influx of Ca<span style="font-family: Arial,Helvetica,sans-serif; font-size: 8px; vertical-align: super;">2+, which activates gelsolin. Gelsolin is an important calcium-dependent protein involved in binding and capping actin at dendritic sites (Hussain, 2001). It is thus an important regulator of cytoskeletal structure involved in plasticity.
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">3.b.c Actin regulation via NMDAR-dependent proteins (Gelsolin and Profilin) **

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">NMDAR is also involved in the regulation of Rho A. NMDAR activation leads to activation of ROCK, the specific kinase of Rho A, which leads to the release of profilin at the targeted spine (Star, 2002). Profilin catalyzes ADP-ATP exchange on ADP-actin monomers, which makes the monomers available for actin polymerization (Bennett, 2011). It is thus also an important regulator of cytoskeletal structure involved in plasticity.

Figure 3. EphB and NMDA receptor dependent actin-modification pathways in dendritic spine. ||
 * [[image:actin_pathways.jpg width="640" height="404"]]


 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px; vertical-align: middle;">Disruption by ADDLs **

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 15px;">

Lacor's paper (2007) showed that solube Abeta-derived oligomers (ADDLs), suspected of being a key component in the neurodegenerative disorder known as Alzheimer’s disease, damage synapses. By using the separation process of fractionation, they showed that ADDLs bind to postsynaptic complexes with NMDAR. However, they did not seem to attach to GABAergic neurons under the same technique, showing specificity towards glutaminergic pyramidal cells.

By treating mature hippocampal neurons with ADDLs, longer exposure led to a decreased density of immunolabeled NR1 and NR2B, subunits of NMDAR, and EphB receptors, labeled with N-terminal [|antibodies].

Long exposure of ADDLs to hippocampal neurons seemed to result in decreased spine density, abnormal spine morphology such as thin filopodia-like and abnormally long (>2 μm) spines and the decrease of cytoskeletal proteins like drebrin. These results strongly suggest ADDLs role in hindering post-synaptic plasticity and supports the idea that ADDLs play a role in Alzheimer's disease, causing decreased cognitive ability.

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