scholarly journals SCAMP5 mediates activity-dependent enhancement of NHE6 recruitment to synaptic vesicles during synaptic plasticity

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Unghwi Lee ◽  
Seung Hyun Ryu ◽  
Sunghoe Chang
Keyword(s):  
Synaptic Plasticity ◽  
Synapse Formation ◽  
Glutamate Release ◽  
Critical Role ◽  
Long Term Potentiation ◽  
Quantal Size ◽  
Term Potentiation ◽  
Presynaptic Boutons ◽  
Activity Dependent

AbstractNa+(K+)/H+ exchanger 6 (NHE6) on synaptic vesicle (SV) is critical for the presynaptic regulation of quantal size at the glutamatergic synapses by converting the chemical gradient (ΔpH) into membrane potential (Δψ) across the SV membrane. We recently found that NHE6 directly interacts with secretory carrier membrane protein 5 (SCAMP5), and SCAMP5-dependent recruitment of NHE6 to SVs controls the strength of synaptic transmission by modulation of quantal size of glutamate release at rest. It is, however, unknown whether NHE6 recruitment by SCAMP5 plays a role during synaptic plasticity. Here, we found that the number of NHE6-positive presynaptic boutons was significantly increased by the chemical long-term potentiation (cLTP). Since cLTP involves new synapse formation, our results indicated that NHE6 was recruited not only to the existing presynaptic boutons but also to the newly formed presynaptic boutons. Knock down of SCAMP5 completely abrogated the enhancement of NHE6 recruitment by cLTP. Interestingly, despite an increase in the number of NHE6-positive boutons by cLTP, the quantal size of glutamate release at the presynaptic terminals remained unaltered. Together with our recent results, our findings indicate that SCAMP5-dependent recruitment of NHE6 plays a critical role in manifesting presynaptic efficacy not only at rest but also during synaptic plasticity. Since both are autism candidate genes, reduced presynaptic efficacy by interfering with their interaction may underlie the molecular mechanism of synaptic dysfunction observed in autism.

scholarly journals Specific Roles of AMPA Receptor Subunit GluR1 (GluA1) Phosphorylation Sites in Regulating Synaptic Plasticity in the CA1 Region of Hippocampus

2010 ◽  
Vol 103 (1) ◽  
pp. 479-489 ◽  
Author(s):  
Hey-Kyoung Lee ◽  
Kogo Takamiya ◽  
Kaiwen He ◽  
Lihua Song ◽  
Richard L. Huganir
Keyword(s):  
Synaptic Plasticity ◽  
Critical Role ◽  
Long Term Potentiation ◽  
Phosphorylation Sites ◽  
Ca1 Region ◽  
Term Potentiation ◽  
Ampa Receptor Subunit ◽  
Glur1 Subunit ◽  
Activity Dependent

Activity-dependent changes in excitatory synaptic transmission in the CNS have been shown to depend on the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). In particular, several lines of evidence suggest that reversible phosphorylation of AMPAR subunit glutamate receptor 1 (GluR1, also referred to as GluA1 or GluR-A) plays a role in long-term potentiation (LTP) and long-term depression (LTD). We previously reported that regulation of serines (S) 831 and 845 on the GluR1 subunit may play a critical role in bidirectional synaptic plasticity in the Schaffer collateral inputs to CA1. Specifically, gene knockin mice lacking both S831 and S845 phosphorylation sites (“double phosphomutants”), where both serine residues were replaced by alanines (A), showed a faster decaying LTP and a deficit in LTD. To determine which of the two phosphorylation sites was responsible for the phenotype, we have now generated two lines of gene knockin mice: one that specifically lacks S831 (S831A mutants) and another that lacks only S845 (S845A mutants). We found that S831A mutants display normal LTP and LTD, whereas S845A mutants show a specific deficit in LTD. Taken together with our previous results from the “double phosphomutants,” our data suggest that either S831 or S845 alone may support LTP, whereas the S845 site is critical for LTD expression.

scholarly journals The Ras-like GTPase Rem2 is a potent endogenous inhibitor of calcium/calmodulin-dependent kinase II activity

2017 ◽  
Author(s):  
Leandro Royer ◽  
Josiah J. Herzog ◽  
Katelyn Kenny ◽  
Boriana Tzvetkova ◽  
Jesse C. Cochrane ◽  
...  
Keyword(s):  
Synapse Formation ◽  
Catalytic Domain ◽  
Physiological Role ◽  
Long Term Potentiation ◽  
Endogenous Inhibitor ◽  
Calcium Calmodulin Dependent ◽  
Term Potentiation ◽  
Cellular Context ◽  
Activity Dependent

AbstractCaMKII is a well-characterized, abundant protein kinase that regulates a diverse set of functions in a tissue specific manner. For example, in heart muscle, CaMKII regulates Ca2+ homeostasis while in neurons CaMKII regulates activity-dependent dendritic remodeling and Long Term Potentiation (LTP), a biological correlate of learning and memory. Previously, we identified the noncanonical GTPase Rem2 as a critical regulator of dendrite branching and synapse formation in the vertebrate nervous system. Here, we report that Rem2 directly interacts with CaMKII and potently inhibits the activity of the intact holoenzyme, a previously undescribed function for the Rem2 protein. To date, only one other endogenous inhibitor of CaMKII has been described: CaMKIIN, which blocks CaMKII activity through binding to the catalytic domain. Our data suggest that Rem2 inhibits CaMKII through a novel mechanism, as inhibition requires the presence of the association domain of CaMKII. Our biochemical finding that Rem2 is a direct, endogenous inhibitor of CaMKII activity, coupled with known functions of Rem2 in neurons, provides a framework which will enable future experiments probing the physiological role of CaMKII inhibition in a cellular context.

scholarly journals Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory

2003 ◽  
Vol 358 (1432) ◽  
pp. 773-786 ◽  
Author(s):  
R. G. M. Morris ◽  
E. I. Moser ◽  
G. Riedel ◽  
S. J. Martin ◽  
J. Sandin ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Cellular Mechanisms ◽  
Memory Processing ◽  
Functional Studies ◽  
Term Potentiation ◽  
Intermediate Storage ◽  
Activity Dependent

The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the ‘synaptic plasticity and memory (SPM)’ hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity.

scholarly journals Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity

2009 ◽  
Vol 37 (6) ◽  
pp. 1369-1374 ◽  
Author(s):  
C. Geoffrey Lau ◽  
Koichi Takeuchi ◽  
Alma Rodenas-Ruano ◽  
Yukihiro Takayasu ◽  
Jessica Murphy ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Extracellular Signals ◽  
Term Potentiation ◽  
A Cell ◽  
Nmdar Subunit ◽  
Higher Cognitive Functions ◽  
Activity Dependent

NMDARs (N-methyl-D-aspartate receptors) are critical for synaptic function throughout the CNS (central nervous system). NMDAR-mediated Ca2+ influx is implicated in neuronal differentiation, neuronal migration, synaptogenesis, structural remodelling, long-lasting forms of synaptic plasticity and higher cognitive functions. NMDAR-mediated Ca2+ signalling in dendritic spines is not static, but can be remodelled in a cell- and synapse-specific manner by NMDAR subunit composition, protein kinases and neuronal activity during development and in response to sensory experience. Recent evidence indicates that Ca2+ permeability of neuronal NMDARs, NMDAR-mediated Ca2+ signalling in spines and induction of NMDAR-dependent LTP (long-term potentiation) at hippocampal Schaffer collateral–CA1 synapses are under control of the cAMP/PKA (protein kinase A) signalling cascade. Thus, by enhancing Ca2+ influx through NMDARs in spines, PKA can regulate the induction of LTP. An emerging concept is that activity-dependent regulation of NMDAR-mediated Ca2+ signalling by PKA and by extracellular signals that modulate cAMP or protein phosphatases at synaptic sites provides a dynamic and potentially powerful mechanism for bi-directional regulation of synaptic efficacy and remodelling.

scholarly journals Activity-dependent netrin-1 secretion drives synaptic insertion of GluA1-containing AMPA receptors in the hippocampus

2018 ◽  
Author(s):  
Stephen D. Glasgow ◽  
Simon Labrecque ◽  
Ian V. Beamish ◽  
Sarah Aufmkolk ◽  
Julien Gibon ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptors ◽  
Long Term Potentiation ◽  
Guidance Cue ◽  
Term Potentiation ◽  
Nmdar Activation ◽  
Genetic Deletion ◽  
Adult Hippocampus ◽  
Activity Dependent

AbstractDynamic trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) to synapses is critical for activity-dependent synaptic plasticity underlying learning and memory, however the identity of key molecular effectors remains elusive. Here, we demonstrate that membrane depolarization and N-methyl-D-aspartate receptor (NMDAR) activation triggers secretion of the chemotropic guidance cue netrin-1 from dendrites. Using selective genetic deletion, we show that netrin-1 expression by excitatory neurons is required for NMDAR-dependent long-term potentiation (LTP) in the adult hippocampus. Further, we demonstrate that application of exogenous netrin-1 is sufficient to trigger the potentiation of excitatory glutamatergic transmission at hippocampal Schaffer collateral synapses via Ca2+-dependent recruitment of GluA1-containing AMPARs, promoting the maturation of immature or nascent synapses. These findings identify a central role for activity-dependent release of netrin-1 as a critical effector of synaptic plasticity in the adult hippocampus.

scholarly journals AMPA receptor trafficking and long-term potentiation

2003 ◽  
Vol 358 (1432) ◽  
pp. 707-714 ◽  
Author(s):  
Roberto Malinow
Keyword(s):  
Ampa Receptor ◽  
Critical Role ◽  
Long Term Potentiation ◽  
Receptor Trafficking ◽  
Synaptic Function ◽  
Term Potentiation ◽  
The Subject ◽  
Activity Dependent ◽  
Ampa Receptor Trafficking

Activity-dependent changes in synaptic function are believed to underlie the formation of memories. A prominent example is long-term potentiation (LTP), whose mechanisms have been the subject of considerable scrutiny over the past few decades. I review studies from our laboratory that support a critical role for AMPA receptor trafficking in LTP and experience-dependent plasticity.

Calcium-Stimulated Adenylyl Cyclases Required for Long-Term Potentiation in the Anterior Cingulate Cortex

2005 ◽  
Vol 94 (1) ◽  
pp. 878-882 ◽  
Author(s):  
Jason Liauw ◽  
Long-Jun Wu ◽  
Min Zhuo
Keyword(s):  
Anterior Cingulate Cortex ◽  
Critical Role ◽  
Cingulate Cortex ◽  
Long Term Potentiation ◽  
Anterior Cingulate ◽  
Adenylyl Cyclases ◽  
Voltage Gated Calcium Channels ◽  
Term Potentiation ◽  
Activity Dependent

Activity-dependent long-term potentiation (LTP) in the CNS is thought to be important in learning, memory, development, and persistent pain. Here, we report that NMDA receptor-dependent LTP is the major form of long-term plasticity in the anterior cingulate cortex (ACC). In addition to N-methyl-d-aspartate (NMDA) receptors, L-type voltage-gated calcium channels are also required for inducing LTP. Activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) is essential for the induction of LTP in ACC neurons, while AC8 subunit partially contributes to forskolin-induced potentiation. Our results suggest that calcium-stimulated cAMP-dependent signaling pathways play a critical role in cingulate LTP.

scholarly journals Somatostatin contributes to long-term potentiation at excitatory synapses onto hippocampal somatostatinergic interneurons

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Anne-Sophie Racine ◽  
François-Xavier Michon ◽  
Isabel Laplante ◽  
Jean-Claude Lacaille
Keyword(s):  
Synaptic Plasticity ◽  
Metabotropic Glutamate Receptors ◽  
Feedback Inhibition ◽  
Critical Role ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Excitatory Synapses ◽  
Term Potentiation ◽  
Dependent Learning

AbstractSomatostatin-expressing interneurons (SOM-INs) are a major subpopulation of GABAergic cells in CA1 hippocampus that receive excitation from pyramidal cells (PCs), and, in turn, provide feedback inhibition onto PC dendrites. Excitatory synapses onto SOM-INs show a Hebbian long-term potentiation (LTP) mediated by type 1a metabotropic glutamate receptors (mGluR1a) that is implicated in hippocampus-dependent learning. The neuropeptide somatostatin (SST) is also critical for hippocampal long-term synaptic plasticity, as well as learning and memory. SST effects on hippocampal PCs are well documented, but its actions on inhibitory interneurons remain largely undetermined. In the present work, we investigate the involvement of SST in long-term potentiation of CA1 SOM-IN excitatory synapses using pharmacological approaches targeting the somatostatinergic system and whole cell recordings in slices from transgenic mice expressing eYFP in SOM-INs. We report that application of exogenous SST14 induces long-term potentiation of excitatory postsynaptic potentials in SOM-INs via somatostatin type 1–5 receptors (SST1-5Rs) but does not affect synapses of PC or parvalbumin-expressing interneurons. Hebbian LTP in SOM-INs was prevented by inhibition of SSTRs and by depletion of SST by cysteamine treatment, suggesting a critical role of endogenous SST in LTP. LTP of SOM-IN excitatory synapses induced by SST14 was independent of NMDAR and mGluR1a, activity-dependent, and prevented by blocking GABAA receptor function. Our results indicate that endogenous SST may contribute to Hebbian LTP at excitatory synapses of SOM-INs by controlling GABAA inhibition, uncovering a novel role for SST in regulating long-term synaptic plasticity in somatostatinergic cells that may be important for hippocampus-dependent memory processes.

Bidirectional Synaptic Plasticity Correlated With the Magnitude of Dendritic Calcium Transients Above a Threshold

2001 ◽  
Vol 85 (1) ◽  
pp. 399-406 ◽  
Author(s):  
R. J. Cormier ◽  
A. C. Greenwood ◽  
J. A. Connor
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Ca1 Neurons ◽  
Test Stimulation ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Before And After ◽  
Activity Dependent ◽  
Stimulation Of

The magnitude of postsynaptic Ca2+ transients is thought to affect activity-dependent synaptic plasticity associated with learning and memory. Large Ca2+ transients have been implicated in the induction of long-term potentiation (LTP), while smaller Ca2+ transients have been associated with long-term depression (LTD). However, a direct relationship has not been demonstrated between Ca2+ measurements and direction of synaptic plasticity in the same cells, using one induction protocol. Here, we used glutamate iontophoresis to induce Ca2+ transients in hippocampal CA1 neurons injected with the Ca2+-indicator fura-2. Test stimulation of one or two synaptic pathways before and after iontophoresis showed that the direction of synaptic plasticity correlated with glutamate-induced Ca2+ levels above a threshold, below which no plasticity occurred (∼180 nM). Relatively low Ca2+ levels (180–500 nM) typically led to LTD of synaptic transmission and higher levels (>500 nM) often led to LTP. Failure to show plasticity correlated with Ca2+ levels in two distinct ranges: <180 nM and ∼450–600 nM, while only LTD occurred between these ranges. Our data support a class of models in which failure of Ca2+ transients to affect transmission may arise either from insufficient Ca2+ to affect Ca2+-sensitive proteins regulating synaptic strength through opposing activities or from higher Ca2+ levels that reset activities of such proteins without affecting the net balance of activities. Our estimates of the threshold Ca2+ level for LTD (∼180 nM) and for the transition from LTD to LTP (∼540 nM) may assist in constraining the molecular details of such models.

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