Molecular Basis of Synaptic Plasticity I Lecture Outline PDF

2024-11-06 Molecular Basis of Synaptic Plasticity I NROC36H3F © Arruda Carvalho UTSC Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP...

2024-11-06 Molecular Basis of Synaptic Plasticity I NROC36H3F © Arruda Carvalho UTSC Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term 1  2024-11-06 What is Synaptic Plasticity? “Synaptic plasticity is the biological process by which specific patterns of synaptic activity result in changes in synaptic strength and is thought to contribute to learning and memory. Both pre-synaptic and post- synaptic mechanisms can contribute to the expression of synaptic plasticity” https://www.nature.com/subjects/synaptic-plasticity © Arruda Carvalho UTSC Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term 2  2024-11-06 Long Term Potentiation (LTP) Bliss and Lomø, J Physiol 1973 © Arruda Carvalho UTSC LTP Long-term potentiation can last for days or even weeks Mechanism by which Memory is Stored? © Arruda Carvalho UTSC 3  2024-11-06 LTP LTP comprises a family of processes that strengthen synaptic transmission through distinct cellular and molecular mechanisms These differ in the relative importance of different receptors, ion channels and second-messenger signaling pathways either in the presynaptic cell (altering release), or in the postsynaptic cell (sensitivity to the neurotransmitter) © Arruda Carvalho UTSC Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term 4  2024-11-06 LTP APV = NMDA receptor antagonist Nitrendipine = L - type Ca2+ channel blocker Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC LTP Presynaptic LTP: Mossy Fiber Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 5  2024-11-06 Presynaptic LTP: Mossy Fiber Tetanus 2 3 1 1. Large Ca2+ influx into the presynaptic terminal 4 2. Activation of a calcium/calmodulin—dependent adenylyl cyclase complex 3. Activation of PKA 4. Increase in glutamate release Nicoll and Schmitz, Nat Rev Neuro 2005 © Arruda Carvalho UTSC LTP in the Mossy Fiber: Non-associative Tetanus 2 3 1 1. Large Ca2+ influx into the presynaptic terminal 4 2. Activation of a calcium/calmodulin—dependent adenylyl cyclase complex 3. Activation of PKA 4. Increase in glutamate release Nicoll and Schmitz, Nat Rev Neuro 2005 © Arruda Carvalho UTSC 6  2024-11-06 Classical Conditioning Recap AC serves as a coincidence detector 1. Siphon touch triggers AP on sensory neuron, leading to Ca2+ influx in presynaptic terminal Activation of Ca2+-sensitive AC (via calmodulin) Mod. From Wang and Storm, Mol Pharm 2003 Increased cAMP production 2. Tail shock leads to 5-HT release onto sensory neuron presynaptic terminal shortly after Further potentiating cAMP production Principles of Neural Science ©McGraw Hill Increased presynaptic facilitation! © Arruda Carvalho UTSC LTP in the Mossy Fiber: Non-associative Tetanus 1. Large Ca2+ influx into the Mossy Fiber LTP is abolished in RIM1 KO (-/-) mice presynaptic terminal 2. Activation of a calcium/calmodulin—dependent adenylyl cyclase complex 3. Activation of PKA Rim1 Phosphorylation Castillo et al., Nature 2002 4. Increase in glutamate release © Arruda Carvalho UTSC 7  2024-11-06 Vesicle Life Cycle Recap 3. Vesicle Fusion 3.1 Docking RIM RIM binds to (1) Munc13 and Rab3/27 to dock vesicle, and (2) to N, P and Q-type Ca2+ channels, tethering them to active zone. PKA phosphorylation of RIM alters its interaction with Rab3 and Munc13 to promote release © Arruda Carvalho UTSC LTP Postsynaptic LTP: Schaeffer Collateral Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 8  2024-11-06 Postsynaptic LTP: Schaeffer Collateral NMDARs are coincidence detectors Functional when: action potentials in the presynaptic neuron release glutamate that binds to the receptor + postsynaptic membrane is sufficiently depolarized to expel Mg2+ Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC Postsynaptic LTP: Schaeffer Collateral Why NMDARs? Ca2+! Increased glutamate release Enhancement in the response of the postsynaptic cell to glutamate How? Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 9  2024-11-06 Postsynaptic LTP: Schaeffer Collateral Activation of protein kinases, including PKC, enhances current through AMPA receptors, in part by causing insertion of new receptors into the synapses Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term 10  2024-11-06 AMPAR Insertion and Silent Synapses Cell b Cell a Alteration in AMPAR number is one of the expression mechanisms for LTP and LTD Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC LTP of Postsynaptic origin and AMPA:NMDA ratios Control LTP AMPAR component AMPAR component Mod from Kauer et al., 1988 AMPAR NMDAR AMPA/NMDA ratio = Amplitude AMPAR response Amplitude NMDAR response © Arruda Carvalho UTSC 11  2024-11-06 AMPAR trafficking AMPARs are inserted into the membrane during NMDAR-dependent LTP Induction of LTP (long-term potentiation) using glycine increases surface GluA1 in cultured hippocampal neurons. Surface GluR1 labelled using an N-terminal GluA1 antibody under nonpermeabilizing conditions in control (upper) and glycine-treated (lower) cultures Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC AMPAR trafficking AMPARs are internalized during NMDAR-dependent LTD Beattie et al., Nat Neuro 2000 © Arruda Carvalho UTSC 12  2024-11-06 AMPAR trafficking: Lateralization AMPARs are mobile in the plasma membrane and in spines Single-molecule tracking traces for individual GluA2 (=GluR2) subunits (left), and an example of the signal from a single molecule (right). Tardin et al., EMBO J 2003 © Arruda Carvalho UTSC AMPAR trafficking: Lateralization Local rises in intracellular calcium decrease GluA2 mobility and accumulate GluA2 in synapses GluA2 diffusion coefficient (top) and surface GluA2 levels (bottom) following the uncaging of a caged calcium ionophore with a train of UV pulses (bar, arrow) Borgdorff & Choquet, Nature 2002 © Arruda Carvalho UTSC 13  2024-11-06 AMPAR trafficking: Lateralization E LTD induction (glutamate in graph) increases synaptic receptor mobility rates (C), decreases their immobility rates (D), and increases the proportion of AMPARs in area close to synapse (=juxtasynaptic) (E) Leads to AMPAR lateral diffusion from synapse to be later internalized in extrasynaptic space Lateral movement of AMPARs in the plasma membrane might be a mechanism for the regulation of AMPAR number during synaptic plasticity Mod from Tardin et al., EMBO J 2003 © Arruda Carvalho UTSC AMPAR trafficking Synaptic plasticity involves both regulated exocytosis and endocytosis of AMPARs at extrasynaptic sites and their regulated lateral diffusion into and out of the synapse, perhaps involving a pool of juxtasynaptic AMPARs that are available for rapid recruitment. Henley and Wilkinson Nat Rev Neuro 2016 © Arruda Carvalho UTSC 14  2024-11-06 AMPAR trafficking Synaptic plasticity involves both regulated exocytosis and endocytosis of AMPARs at extrasynaptic sites and their regulated lateral diffusion into and out of the synapse, perhaps involving a pool of juxtasynaptic AMPARs that are available for rapid recruitment. What mechanisms drive AMPARs into and out of synapses during LTP and LTD through exocytosis, endocytosis and lateral diffusion? © Arruda Carvalho UTSC AMPAR trafficking: Mechanisms PSD95 and TARPs NSF and AP2 PICK1 and ABP/GRIP SAP97 and Myosin VI Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC 15  2024-11-06 AMPAR trafficking: Mechanisms PSD95 and TARPs NSF and AP2 PICK1 and ABP/GRIP SAP97 and Myosin VI Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC Recap AMPAR trafficking: Mechanisms PSD95 and Tarps Tomita et al., J. Cell Biol 2001 “The interaction of stargazin with AMPA receptor subunits is essential for delivering functional receptors to the surface membrane of granule cells, whereas its binding with PSD-95 and related PDZ proteins is required for targeting the AMPA receptor to synapses” © Arruda Carvalho UTSC 16  2024-11-06 AMPAR trafficking: Mechanisms PSD95 and TARPs NSF and AP2 PICK1 and ABP/GRIP SAP97 and Myosin VI Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC AMPAR trafficking: Mechanisms Recap N-ethylmaleimide-sensitive fusion protein (NSF) and Soluble NSF-attachment protein (SNAP) NSF dissociate SNARE complexes Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 17  2024-11-06 AMPAR trafficking: Mechanisms NSF Disruption of the NSF–GluA2 protein–protein interaction by introducing the G10 peptide into the postsynaptic cell caused a decrease in mEPSC amplitude and frequency compared to the control peptide S10 Luscher et al., Neuron 1999 © Arruda Carvalho UTSC AMPAR trafficking: Mechanisms NSF The association between NSF and GluA2 is important to maintain AMPARs at synapses Disruption of the NSF–GluA2 protein–protein interaction by introducing the G10 peptide into the postsynaptic cell caused a decrease in mEPSC amplitude and frequency and in the surface expression of AMPARs compared to the control peptide S10 Luscher et al., Neuron 1999 © Arruda Carvalho UTSC 18  2024-11-06 AMPAR trafficking: Mechanisms NSF vs AP2 The association between NSF and GluA2 is important to maintain AMPARs at synapses The AP2 adaptor complex binds to an overlapping region of GluA2; NSF probably occupies the site to stabilize receptors at synapses, but in response to an appropriate stimulus, it is replaced by AP2, which then initiates clathrin-dependent internalization Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC AMPAR trafficking: Mechanisms PSD95 and TARPs NSF and AP2 PICK1 and ABP/GRIP SAP97 and Myosin VI Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC 19  2024-11-06 AMPAR trafficking: Mechanisms PICK1 vs ABP/GRIP In basal conditions, the C-terminal PDZ domain of GluA2 may be bound to either ABP/GRIP or to PICK1 (protein interacting with C-kinase) ABP/GRIP tethers AMPARs to synapses PICK1 can bind the C-terminus of GluA2 and target PKCα to phosphorylate serine 880 of GluA2 Once phosphorylated at this residue, GluA2 can bind PICK1 but not ABP/GRIP, thus providing a mechanism by which AMPARs can be freed from ABP/GRIP for internalization Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC AMPAR trafficking: Mechanisms PICK1 In basal conditions, the C-terminal PDZ domain of GluA2 may be bound to either ABP/GRIP or to PICK1. Upon LTD, this equilibrium is shifted in favour of binding to PICK1 PICK1 is also involved in subsequent recycling of AMPARs back to the plasma PICK1 drives the membrane endocytosis of GluA2- containing AMPARs next to the PSD Internalized AMPARs are kept at an intracellular location by ABP/GRIP Hanley, Pharm & Therap 2008 © Arruda Carvalho UTSC 20  2024-11-06 AMPAR trafficking: Mechanisms PSD95 and TARPs NSF and AP2 PICK1 and ABP/GRIP SAP97 and Myosin VI Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC AMPAR trafficking: Mechanisms SAP97 and myosin VI Synapse-associated protein 97 (SAP97) binds to the GluA1 PDZ domain, and to the motor protein myosin VI. CaMKII phosphorylation of SAP97 triggers GluA1 traffic to the synapse Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC 21  2024-11-06 AMPAR trafficking: Mechanisms Collingridge et al., Nat Rev Neuro 2004 © Arruda Carvalho UTSC AMPAR trafficking: Mechanisms Carroll et al., Nat Rev Neuro 2001 © Arruda Carvalho UTSC 22  2024-11-06 Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term Early and Late LTP One train of action potentials produces a phase of LTP lasting 1 to 3 hours called early LTP. However, four or more trains of synaptic stimulation induce a late LTP that lasts up to 24 hours. Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 23  2024-11-06 Early and Late LTP Early LTP does not require new protein Late LTP does require cAMP and PKA, as synthesis, cAMP, or PKA activation well as changes in gene transcription and the synthesis of new proteins Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC Early and Late LTP: What’s the Difference? Prior to LTP a CA3 neuron typically forms only one functional synapse with a CA1 neuron (B). At this synapse a presynaptic action potential releases with low probability a single vesicle of transmitter Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 24  2024-11-06 Early and Late LTP: What’s the Difference? Following induction of early LTP, the probability that a presynaptic action potential will release a vesicle is increased Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC Early and Late LTP: What’s the Difference? Sp-cAMPS = chemical analog of cAMP Anisomycin = protein synthesis inhibitor Following late LTP, a presynaptic action potential elicits a very large EPSP through the release of multiple quanta of transmitter. This is a result of growth of new connections (new presynaptic release sites apposed to new clusters of AMPA receptors in the postsynaptic membrane, a protein synthesis dependent process) Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 25  2024-11-06 Early and Late LTP Late phase of LTP in the Schaffer collateral pathway AC Late LTP: Ca2+ influx recruits AC, leading to PKA-mediated CREB activation and consequent structural changes Early LTP: activation of NMDA receptors, Ca2+ influx Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC LTP Maintenance: PKM PKMζ is an isoform of protein kinase C which lacks a regulatory domain and is thus constitutively active Levels of PKMζ in the hippocampus are normally low. Tetanic stimulation leads to an increase in translation of PKMζ mRNA. This mRNA is present in the CA1 neuron dendrites, enabling its local translation to rapidly alter synaptic strength through enhancing AMPAR membrane insertion Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 26  2024-11-06 LTP Maintenance: PKM PKMζ enhances the actions of NSF, preventing postsynaptic removal of GluA2 Sacktor, Nature Rv Neuro, 2011 © Arruda Carvalho UTSC Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term 27  2024-11-06 Molecular basis of LTD NMDAR- LTD mGluR5- LTD Collingridge et al., Nat Rev Neuro 2010 © Arruda Carvalho UTSC Molecular basis of LTD NMDAR- LTD 2 1 Collingridge et al., Nat Rev Neuro 2010 a. Calmodulin (CaM) detects Ca2+ (graded purple clouds) that enters via NMDARs and this leads, through a Ser/Thr protein phosphatase cascade, to activation of protein phosphatase 1 (PP1) a key enzyme in synaptically-induced LTD. PP1 can dephosphorylate various targets, including (1) ser845 on the AMPAR subunit GluA1, leading to internalization; and (2) ser295 of PSD95 - enabling its removal from the synapse and thereby permitting AMPAR endocytosis. © Arruda Carvalho UTSC 28  2024-11-06 Molecular basis of LTD mGluR5- LTD Collingridge et al., Nat Rev Neuro 2010 a. mGluR5 activation leads to activation of PLC. This can trigger the release of Ca2+ from intracellular stores and the activation of PKC. In some forms of mGluR- LTD, PICK1 may target PKCα to phosphorylate ser880 of GluA2 to displace ABP– GRIP and promote the removal of AMPARs from synapses. © Arruda Carvalho UTSC Molecular basis of LTD mGluR5- LTD Collingridge et al., Nat Rev Neuro 2010 d, f. mGluR-LTD has been shown to require rapid (in a few minutes) local de novo protein synthesis, which depends on the PI3K-Akt-mTOR pathway. An important protein being translated is Arc, thought to help initiate dynamin-dependent endocytosis of AMPARs. © Arruda Carvalho UTSC 29  2024-11-06 Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term LTP, LTD and Memory Long-term potentiation can last for days or even weeks Mechanism by which Memory is Stored? What is the relationship between LTP and Memory? © Arruda Carvalho UTSC 30  2024-11-06 LTP and Memory: Causal Link? Tone CS (a) or optical CS pairing with a footshock (b) leads to a conditioned response (reduction in lever presses) Tone Blue light Optical CS pairing with US leads to postsynaptic strengthening in this pathway (c) Optical CS = stimulation of medial geniculate nucleus and auditory cortex inputs to lateral amygdala with excitatory opsin oChief CS = conditioned stimulus US = unconditioned stimulus – foot shock Nabavi, Fox et al., Nature 2014 © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term LTP and Memory: Causal Link? LTD protocol reversed optical conditioning (b); LTP protocol reinstates conditioned responses (c) Nabavi, Fox et al., Nature 2014 © Arruda Carvalho UTSC 31  2024-11-06 LTP and Memory: Causal Link? LTD protocol decreased CR in tone-conditioned animals Nabavi, Fox et al., Nature 2014 © Arruda Carvalho UTSC Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term 32  2024-11-06 Experience Dependent Plasticity Structural and functional changes of neuronal circuits in response to experience Hensch, Nat Rev Neuro 2005 © Arruda Carvalho UTSC Experience Dependent Plasticity: Fear Pavlovian classical conditioning modifies the strength of synaptic transmission in lateral amygdala Principles of Neural Science ©McGraw Hill © Arruda Carvalho UTSC 33  2024-11-06 Experience Dependent Plasticity: Fear Potentiation of thalamic afferents to LA neurons after auditory fear conditioning in mice Clem and Huganir, Science, 2010 © Arruda Carvalho UTSC Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term 34  2024-11-06 Recap AMPAR Subunit Composition Sobolevsky et al., Nature, 2009 GluA4 Mod from Henley and Wilkinson, Dial Clin Neurosci, 2013 © Arruda Carvalho UTSC Measurements of Postsynaptic Plasticity Rectification AMPAR subunit GluA1/3/4 GluA2 slope neg potentials Rectification Index = =1 slope pos potentials Liu and Cull-Candy, 2002 GluA2-lacking AMPAR decrease in conductance at positive potentials © Arruda Carvalho UTSC 35  2024-11-06 Experience Dependent Plasticity: Fear There is an accumulation of GluA2-lacking (cp-AMPARs) in LA following fear conditioning Clem and Huganir, Science, 2010 © Arruda Carvalho UTSC cp-AMPARs and Plasticity Shepherd, Front Mol Neurosci 2012 © Arruda Carvalho UTSC 36  2024-11-06 Reconsolidation Update Successfully Erases Fear Memories in Mice, Rats and Humans In Rats Monfils et al., Science 2009 © Arruda Carvalho UTSC Reconsolidation Update Successfully Erases Fear Memories in Mice, Rats and Humans 1 year later Schiller et al., Nature 2010 © Arruda Carvalho UTSC 37  2024-11-06 Reconsolidation Update Successfully Erases Fear Memories in Mice, Rats and Humans How??? Clem and Huganir, Science, 2010 © Arruda Carvalho UTSC Reconsolidation Update Dampens Amygdala Transmission via Removal of Synaptic Cp-AMPARs Clem and Huganir, Science, 2010 © Arruda Carvalho UTSC 38  2024-11-06 Reconsolidation Update Dampens Amygdala Transmission via Removal of Synaptic Cp-AMPARs Clem and Huganir, Science, 2010 © Arruda Carvalho UTSC Regulation of cp-AMPAR (GluA2-lacking) trafficking = cp-AMPAR PICK1 interacts with the PDZ domain of GluA2 and GluA3. Upon LTP, PICK1 can limit AMPAR recycling to GluA2-containing AMPARs, thereby promoting the switch to synaptic CP-AMPARs Henley and Wilkinson Nat Rev Neuro 2016 © Arruda Carvalho UTSC 39  2024-11-06 Regulation of cp-AMPAR trafficking = cp-AMPAR During LTP, activation of PKA leads to phosphorylation of GluA1 at S845, stabilizing GluA1 homomers, promoting its surface expression Henley and Wilkinson Nat Rev Neuro 2016 © Arruda Carvalho UTSC Regulation of cp-AMPAR trafficking = cp-AMPAR Dephosphorylation of GluA1 S845 is associated with NMDAR- dependent LTD, suggesting that the removal of CP-AMPARs contributes to these form of LTD, and that the phosphorylation state of GluA1 S845 may control the supply of extrasynaptic CP-AMPARs for bidirectional synaptic plasticity Henley and Wilkinson Nat Rev Neuro 2016 © Arruda Carvalho UTSC 40  2024-11-06 Targeted mutation to GluA1 S845 blocks Reconsolidation Update S845A mutation: GluA1 replaced Ser845 for Ala, cannot be phosphorylated Clem and Huganir, Science, 2010 © Arruda Carvalho UTSC Recap Molecular basis of LTD 1 Collingridge et al., Nat Rev Neuro 2010 a. Calmodulin (CaM) detects Ca2+ (graded purple clouds) that enters via NMDARs and this leads, through a Ser/Thr protein phosphatase cascade, to activation of protein phosphatase 1 (PP1) a key enzyme in synaptically-induced LTD. PP1 can dephosphorylate various targets, including (1) ser845 on the AMPAR subunit GluA1, leading to internalization; and (2) ser295 of PSD95 - enabling its removal from the synapse and thereby permitting AMPAR endocytosis. © Arruda Carvalho UTSC 41  2024-11-06 Lecture Outline Synaptic Plasticity LTP Types of LTP AMPAR Trafficking Stages of LTP Early LTP Late LTP Molecular Basis of LTD LTP/LTD and Memory? Experience Dependent Plasticity Calcium Permeable AMPARs © Arruda Carvalho UTSC © 2018 Arruda Carvalho UTSC winter term 42