scholarly journals p97 regulates GluA1 homomeric AMPA receptor formation and plasma membrane expression

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuan Ge ◽  
Meng Tian ◽  
Lidong Liu ◽  
Tak Pan Wong ◽  
Bo Gong ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Long Term Potentiation ◽  
Postsynaptic Membrane ◽  
Mammalian Brain ◽  
Membrane Expression ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Plasma Membrane Expression

Abstract The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs) mediate the fast excitatory synaptic transmission in the mammalian brain and are important for synaptic plasticity. In particular, the rapid insertion of the GluA1 homomeric (GluA1-homo) AMPARs into the postsynaptic membrane is considered to be critical in the expression of hippocampal CA1 long-term potentiation (LTP), which is important for certain forms of learning and memory. However, how the formation and trafficking of GluA1-homo AMPARs are regulated remains poorly understood. Here, we report that p97 specifically interacts with and promotes the formation of GluA1-homo AMPARs. The association with p97 retains GluA1-homo AMPARs in the intracellular compartment under basal conditions, and its dissociation allows GluA1-homo AMPARs to be rapidly inserted into the postsynaptic membrane shortly after LTP induction. Thus, our results shed lights into the molecular mechanisms by which p97 regulates GluA1-homo AMPARs formation and trafficking, thereby playing a critical role in mediating synaptic plasticity.

scholarly journals Chronic neuronal excitation leads to homeostatic suppression of structural long-term potentiation

2021 ◽  
Author(s):  
Hiromi H Ueda ◽  
Aiko Sato ◽  
Maki Onda ◽  
Hideji Murakoshi
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Homeostatic Plasticity ◽  
Ca1 Neurons ◽  
Downstream Signaling ◽  
Neuronal Excitation ◽  
Term Potentiation ◽  
Hippocampal Ca1

Synaptic plasticity is long-lasting changes in synaptic currents and structure. When neurons are exposed to signals that induce aberrant neuronal excitation, they increase the threshold for the induction of synaptic plasticity, called homeostatic plasticity. To further understand the homeostatic regulation of synaptic plasticity and its molecular mechanisms, we investigated glutamate uncaging/photoactivatable (pa)CaMKII-dependent sLTP induction in hippocampal CA1 neurons after chronic neuronal excitation by GABAA receptor antagonists. The neuronal excitation suppressed the glutamate uncaging-evoked Ca2+ influx and failed to induce sLTP. Single-spine optogenetic stimulation using paCaMKII also failed to induce sLTP, suggesting that CaMKII downstream signaling is impaired in response to chronic neuronal excitation. Furthermore, while the inhibition of Ca2+ influx was protein synthesis-independent, paCaMKII-induced sLTP depended on it. Our findings demonstrate that chronic neuronal excitation suppresses sLTP in two independent ways (i.e., the inhibitions of Ca2+ influx and CaMKII downstream signaling), which may contribute to the robust neuronal protection in excitable environments.

scholarly journals In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus

2003 ◽  
Vol 358 (1432) ◽  
pp. 757-763 ◽  
Author(s):  
Christopher Pittenger ◽  
Eric R. Kandel
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Mammalian Brain ◽  
Marine Snail ◽  
Synaptic Facilitation ◽  
Term Potentiation ◽  
Two Systems ◽  
Mechanisms Of Plasticity

Long-term synaptic plasticity is thought to underlie many forms of long-lasting memory. Long-lasting plasticity has been most extensively studied in the marine snail Aplysia and in the mammalian hippocampus, where Bliss and Lømo first described long-term potentiation 30 years ago. The molecular mechanisms of plasticity in these two systems have proven to have many similarities. Here, we briefly describe some of these areas of overlap. We then summarize recent advances in our understanding of the mechanisms of long-lasting synaptic facilitation in Aplysia and suggest that these may prove fruitful areas for future investigation in the mammalian hippocampus and at other synapses in the mammalian brain.

scholarly journals Altered Short-Term Synaptic Plasticity in Mice Lacking the Metabotropic Glutamate Receptor mGlu7

2002 ◽  
Vol 2 ◽  
pp. 730-737 ◽  
Author(s):  
Trevor J. Bushell ◽  
Gilles Sansig ◽  
Valerie J. Collett ◽  
Herman van der Putten ◽  
Graham L. Collingridge
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Short Term ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Commissural Pathway ◽  
Frequency Facilitation

Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/- mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/- mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/- mouse. In addition, there was less frequency facilitation during, and less post-tetanic potentiation following, a high frequency train in the mGlu7-/- mouse. These results show that the absence of mGlu7 receptors results in alterations in short-term synaptic plasticity in the hippocampus.

scholarly journals (2S,6S)- and (2R,6R)-hydroxynorketamine inhibit the induction of NMDA receptor-dependent LTP at hippocampal CA1 synapses in mice

2020 ◽  
Vol 4 ◽  
pp. 239821282095784
Author(s):  
Heather Kang ◽  
Pojeong Park ◽  
Muchun Han ◽  
Patrick Tidball ◽  
John Georgiou ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Long Term Potentiation ◽  
Aspartate Receptor ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Mouse Hippocampus ◽  
Site Of Action ◽  
A Site

The ketamine metabolite (2 R,6 R)-hydroxynorketamine has been proposed to have rapid and persistent antidepressant actions in rodents, but its mechanism of action is controversial. We have compared the ability of ( R,S)-ketamine with the (2 S,6 S)- and (2 R,6 R)-isomers of hydroxynorketamine to affect the induction of N-methyl-d-aspartate receptor–dependent long-term potentiation in the mouse hippocampus. Following pre-incubation of these compounds, we observed a concentration-dependent (1–10 μM) inhibition of long-term potentiation by ketamine and a similar effect of (2 S,6 S)-hydroxynorketamine. At a concentration of 10 μM, (2 R,6 R)-hydroxynorketamine also inhibited the induction of long-term potentiation. These findings raise the possibility that inhibition of N-methyl-d-aspartate receptor–mediated synaptic plasticity is a site of action of the hydroxynorketamine metabolites with respect to their rapid and long-lasting antidepressant-like effects.

scholarly journals GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

2003 ◽  
Vol 358 (1432) ◽  
pp. 715-720 ◽  
Author(s):  
Fabrice Duprat ◽  
Michael Daw ◽  
Wonil Lim ◽  
Graham Collingridge ◽  
John Isaac
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Protein Interactions ◽  
Ampa Receptors ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Mammalian Brain ◽  
Protein Protein Interactions ◽  
Term Potentiation

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.

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.

Silent glutamatergic synapses in the mammalian brain

1999 ◽  
Vol 77 (9) ◽  
pp. 735-737 ◽  
Author(s):  
John TR Isaac ◽  
Roger A Nicoll ◽  
Robert C Malenka
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptors ◽  
Neural Activity ◽  
Long Term Potentiation ◽  
Mammalian Brain ◽  
Glutamatergic Synapses ◽  
Synaptic Localization ◽  
Term Potentiation ◽  
Ampa And Nmda Receptors

Excitatory synaptic transmission in the mammalian brain is mediated primarily by α-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors that are thought to be co-localized at individual synapses. However, recent electrophysiological and anatomical data suggest that the synaptic localization of AMPA and NMDA receptors may be independently regulated by neural activity. These data are reviewed here and the implications of these findings for the mechanisms underlying synaptic plasticity are discussed.Key words: glutamate receptor, long-term potentiation (LTP), synaptic plasticity, hippocampus, cortex.

scholarly journals Dissecting the Roles of Kalirin-7/PSD95/GluN2B Interactions in Different Forms of Synaptic Plasticity

2019 ◽  
Author(s):  
Mason L. Yeh ◽  
Jessica R. Yasko ◽  
Eric S. Levine ◽  
Betty A. Eipper ◽  
Richard E. Mains
Keyword(s):  
Synaptic Plasticity ◽  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Postsynaptic Density ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Multiple Components ◽  
Term Potentiation ◽  
Knockout Animals

AbstractKalirin-7 (Kal7) is a Rac1/RhoG GEF and multidomain scaffold localized to the postsynaptic density which plays an important role in synaptic plasticity. Behavioral and physiological phenotypes observed in the Kal7 knockout mouse are quite specific: genetics of breeding, growth, strength and coordination are normal; Kal7 knockout animals self-administer cocaine far more than normal mice, show exaggerated locomotor responses to cocaine, but lack changes in dendritic spine morphology seen in wildtype mice; Kal7 knockout mice have depressed surface expression of GluN2B receptor subunits and exhibit marked suppression of long-term potentiation and depression in hippocampus, cerebral cortex, and spinal cord; and Kal7 knockout mice have dramatically blunted perception of pain. To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we administered intracellular blocking peptides to acutely change Kal7 function at the synapse, to determine if plasticity deficits in Kal7-/-mice are the product of developmental processes since conception, or could be detected on a much shorter time scale. We found that specific disruption of the interactions of Kal7 with PSD-95 or GluN2B resulted in significant suppression of long-term potentiation and long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.Graphical Table of ContentsThe postsynaptic density is an integral player in receiving, interpreting and storing signals transmitted by presynaptic terminals. The correct molecular composition is crucial for successful expression of synaptic plasticity. Key components of the postsynaptic density include ligand-gated ion channels, structural and binding proteins, and multidomain scaffolding plus enzymatic proteins. These studies address whether the multiple components of the synaptic density bind together in a static or slowly adapting molecular complex, or whether critical interactions are fluid on a minute-to-minute basis.

scholarly journals Dissecting the Roles of Kalirin-7/PSD-95/GluN2B Interactions in Different Forms of Synaptic Plasticity

2020 ◽  
Author(s):  
Mason L. Yeh ◽  
Jessica R Yasko ◽  
Eric S. Levine ◽  
Betty A. Eipper ◽  
Richard Mains
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Synaptic Function ◽  
Nucleotide Exchange ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Knockout Animals

Abstract Background: Kalirin-7 (Kal7) is a multidomain scaffold and guanine nucleotide exchange factor localized to the postsynaptic density, where Kal7 is crucial for synaptic plasticity. Kal7 knockout mice exhibit marked suppression of long-term potentiation and long-term depression in hippocampus, cerebral cortex and spinal cord, with depressed surface expression of GluN2B receptor subunits and dramatically blunted perception of pain. Kal7 knockout animals show exaggerated locomotor responses to psychostimulants and self-administer cocaine more enthusiastically than wildtype mice. Results: To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we infused candidate intracellular interfering peptides to acutely challenge the synaptic function(s) of Kal7 with potential protein binding partners, to determine if plasticity deficits in Kal7-/- mice are the product of developmental processes since conception, or could be produced on a much shorter time scale. We demonstrated that these small intracellular peptides disrupted normal long-term potentiation and long-term depression, strongly suggesting that maintenance of established interactions of Kal7 with PSD-95 and/or GluN2B is crucial to synaptic plasticity. Conclusions: Blockade of the Kal7-GluN2B interaction was most effective at blocking long-term potentiation, but had no effect on long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.

Estrogen and hippocampal synaptic plasticity

2004 ◽  
Vol 1 (4) ◽  
pp. 327-338 ◽  
Author(s):  
MICHAEL FOY ◽  
MICHEL BAUDRY ◽  
RICHARD THOMPSON
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Estrogen Therapy ◽  
Long Term Potentiation ◽  
Neural Function ◽  
Term Potentiation ◽  
Primary Focus

During the past several years, there has been increasing interest in the effects of estrogen on neural function. This enthusiasm is driven, in part, by the results of early clinical studies suggesting that estrogen therapy given after menopause may prevent, or at least delay, the onset of Alzheimer's disease in older women. However, later clinical trials of women with probable Alzheimer's disease had contrary results. Much of the current research related to estrogen and brain function is focused in two directions. One involves clinical studies that examine the potential of estrogen in protecting against cognitive decline during normal aging and against Alzheimer's disease (neuroprotection). The other direction, which is the primary focus of this review, involves laboratory studies that examine the mechanisms by which estrogen can modify the structure of nerve cells and alter the way neurons communicate with other cells in the brain (neuroplasticity). In this review, we examine recent evidence from experimental and clinical research on the rapid effects of estrogen on several mechanisms that involve synaptic plasticity in the nervous system, including hippocampal excitability, long-term potentiation and depression related to sex and aging differences, cellular neuroprotection and probable molecular mechanisms of the action of estrogen in brain tissue.

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