Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling

AbstractStructural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity in hippocampal CA1 neurons from mice and rats, we demonstrate that p38 MAPK is required downstream of conformational NMDAR signaling to drive both spine shrinkage and LTD at individual dendritic spines. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP and nNOS, nNOS enzymatic activity, activation of MK2 and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that drive the shrinkage and elimination of dendritic spines during synaptic plasticity.

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A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability

Molecular Brain ◽

10.1186/s13041-020-0545-1 ◽

2020 ◽

Vol 13 (1) ◽

Cited By ~ 5

Author(s):

Lyndsey M. Konen ◽

Amanda L. Wright ◽

Gordon A. Royle ◽

Gary P. Morris ◽

Benjamin K. Lau ◽

...

Keyword(s):

Nmda Receptor ◽

Learning And Memory ◽

Rna Editing ◽

Dendritic Spines ◽

Mouse Line ◽

Neuron Loss ◽

Memory Impairments ◽

Hippocampal Ca1

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Distinct Ca 2+ Sources in Dendritic Spines of Hippocampal CA1 Neurons Couple to SK and K v 4 Channels

Neuron ◽

10.1016/j.neuron.2013.11.004 ◽

2014 ◽

Vol 81 (2) ◽

pp. 379-387 ◽

Cited By ~ 28

Author(s):

Kang Wang ◽

Mike T. Lin ◽

John P. Adelman ◽

James Maylie

Keyword(s):

Dendritic Spines ◽

Ca1 Neurons ◽

Hippocampal Ca1 Neurons ◽

Hippocampal Ca1

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Cyclic changes in NMDA receptor activation in hippocampal CA1 neurons after ischemia

Neuroscience Research ◽

10.1016/s0168-0102(97)00096-5 ◽

1997 ◽

Vol 29 (4) ◽

pp. 273-281 ◽

Cited By ~ 4

Author(s):

K Oguro ◽

T Miyawaki ◽

H Cho ◽

H Yokota ◽

T Masuzawa ◽

...

Keyword(s):

Nmda Receptor ◽

Receptor Activation ◽

Ca1 Neurons ◽

Hippocampal Ca1 Neurons ◽

Hippocampal Ca1 ◽

Cyclic Changes ◽

Nmda Receptor Activation

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Hypoxia with inflammation and reperfusion alters membrane resistance by dynamically regulating voltage-gated potassium channels in hippocampal CA1 neurons

Molecular Brain ◽

10.1186/s13041-021-00857-9 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yoon-Sil Yang ◽

Joon Ho Choi ◽

Jong-Cheol Rah

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Neuronal Damage ◽

Input Resistance ◽

Delayed Rectifier ◽

Hcn Channels ◽

Neural Function ◽

Ca1 Neurons ◽

Hippocampal Ca1 Neurons ◽

Hippocampal Ca1

AbstractHypoxia typically accompanies acute inflammatory responses in patients and animal models. However, a limited number of studies have examined the effect of hypoxia in combination with inflammation (Hypo-Inf) on neural function. We previously reported that neuronal excitability in hippocampal CA1 neurons decreased during hypoxia and greatly rebounded upon reoxygenation. We attributed this altered excitability mainly to the dynamic regulation of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels and input resistance. However, the molecular mechanisms underlying input resistance changes by Hypo-Inf and reperfusion remained unclear. In the present study, we found that a change in the density of the delayed rectifier potassium current (IDR) can explain the input resistance variability. Furthermore, voltage-dependent inactivation of A-type potassium (IA) channels shifted in the depolarizing direction during Hypo-Inf and reverted to normal upon reperfusion without a significant alteration in the maximum current density. Our results indicate that changes in the input resistance, and consequently excitability, caused by Hypo-Inf and reperfusion are at least partially regulated by the availability and voltage dependence of KV channels. Moreover, these results suggest that selective KV channel modulators can be used as potential neuroprotective drugs to minimize hypoxia- and reperfusion-induced neuronal damage.

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

10.1101/2021.03.16.435575 ◽

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.

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Neuronal hibernation following hippocampal demyelination

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01130-9 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Selva Baltan ◽

Safdar S. Jawaid ◽

Anthony M. Chomyk ◽

Grahame J. Kidd ◽

Jacqueline Chen ◽

...

Keyword(s):

Dendritic Spines ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Three Dimensional ◽

Long Term Potentiation ◽

Synaptic Function ◽

Mammalian Brain ◽

Gene Transcript ◽

Ca1 Neurons

AbstractCognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca2+-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.

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