KIF2C regulates synaptic plasticity and cognition by mediating dynamic microtubule invasion of dendritic spines

Dynamic microtubules play a critical role in cell structure and function. In nervous system, microtubules specially extend into and out of synapses to regulate synaptic development and plasticity. However, the detailed polymerization especially the depolymerization mechanism that regulates dynamic microtubules in synapses is still unclear. In this study, we find that KIF2C, a dynamic microtubule depolymerization protein without known function in the nervous system, plays a vital role in the structural and functional plasticity of synapses and regulates cognitive function. Using RNAi knockdown and conditional knockout approaches, we showed that KIF2C regulates spine morphology and synaptic membrane expression of AMPA (α- amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors. Moreover, KIF2C deficiency leads to impaired excitatory transmission, long-term potentiation, and altered cognitive behaviors in mice. Mechanistically, KIF2C regulates microtubule dynamics and microtubule invasion of spines in neurons by its microtubule depolymerization capability in a neuronal activity-dependent manner. This study explores a novel function of KIF2C in the nervous system and provides an important regulatory mechanism on how microtubule invasion of spines regulates synaptic plasticity and cognition behaviors.

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Interleukin-6 Derived from the Central Nervous System May Influence the Pathogenesis of Experimental Autoimmune Encephalomyelitis in a Cell-Dependent Manner

Cells ◽

10.3390/cells9020330 ◽

2020 ◽

Vol 9 (2) ◽

pp. 330 ◽

Cited By ~ 4

Author(s):

Paula Sanchis ◽

Olaya Fernández-Gayol ◽

Gemma Comes ◽

Anna Escrig ◽

Mercedes Giralt ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Experimental Autoimmune Encephalomyelitis ◽

Interleukin 6 ◽

Critical Role ◽

Cell Types ◽

Minor Role ◽

Dependent Manner ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

Background: Interleukin-6 (IL-6) is a pleiotropic and multifunctional cytokine that plays a critical role in induction of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Although EAE has always been considered a peripherally elicited disease, Il6 expression exclusively within central nervous system is sufficient to induce EAE development. Neurons, astrocytes, and microglia can secrete and respond to IL-6. Methods: To dissect the relevance of each cell source for establishing EAE, we generated and immunized conditional Il6 knockout mice for each of these cell types with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) peptide dissolved in complete Freund’s adjuvant (CFA) and supplemented with Mycobacterium tuberculosis. Results and conclusions: The combined results reveal a minor role for Il6 expression in both astrocytes and microglia for symptomatology and neuropathology of EAE, whereas neuronal Il6 expression was not relevant for the variables analyzed.

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

Journal of Neurophysiology ◽

10.1152/jn.00835.2009 ◽

2010 ◽

Vol 103 (1) ◽

pp. 479-489 ◽

Cited By ~ 143

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.

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Inhibition of Endoplasmic Reticulum Stress Reverses Synaptic Plasticity Deficits in Striatum of DYT1 Dystonia Mice

10.21203/rs.3.rs-166434/v1 ◽

2021 ◽

Author(s):

Huaying Cai ◽

Linhui Ni ◽

Xingyue Hu ◽

Xianjun Ding

Keyword(s):

Endoplasmic Reticulum ◽

Synaptic Plasticity ◽

Er Stress ◽

Critical Role ◽

Stress Protein ◽

Long Term Potentiation ◽

Research Field ◽

Protein Levels ◽

Dyt1 Dystonia

Abstract Background & objectiveStriatal plasticity alterations caused by endoplasmic reticulum (ER) stress is supposed to be critically involved in the mechanism of DYT1 dystonia. In the current study, we expanded this research field by investigating the critical role of ER stress underlying synaptic plasticity impairment imposed by mutant heterozygous Tor1a+/- in a DYT1 dystonia mouse model.Methods & resultsLong-term depression (LTD) was failed to be induced, while long-term potentiation (LTP) was further strengthened in striatal spiny neurons (SPNs) from the Tor1a+/- DYT1 dystonia mice. Spine morphology analyses revealed a significant increase of both number of mushroom type spines and spine width in Tor1a+/- SPNs. In addition, increased AMPA receptor function and the reduction of NMDA/AMPA ratio in the postsynaptic of Tor1a+/- SPNs was observed, along with increased ER stress protein levels in Tor1a+/- striatum. Notably, ER stress inhibitors, tauroursodeoxycholic acid (TUDCA), could rescue LTD as well as AMPA currents.ConclusionThe current study illustrated the role of ER stress in mediating structural and functional plasticity alterations in Tor1a+/- SPNs. Inhibition of the ER stress by TUDCA is beneficial in reversing the deficits at the cellular and molecular levels. Remedy of dystonia associated neurological and motor functional impairment by ER stress inhibitors could be a recommendable therapeutic agent in clinical practice.

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The effect of NAMPT deletion in projection neurons on the function and structure of neuromuscular junction (NMJ) in mice

Scientific Reports ◽

10.1038/s41598-019-57085-4 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Samuel Lundt ◽

Nannan Zhang ◽

Xiaowan Wang ◽

Luis Polo-Parada ◽

Shinghua Ding

Keyword(s):

Neuromuscular Junction ◽

Synaptic Vesicle ◽

Critical Role ◽

Conditional Knockout ◽

High Frequency Stimulation ◽

Mitochondrial Morphology ◽

Projection Neurons ◽

Dependent Manner ◽

Nicotinamide Phosphoribosyltransferase ◽

The Impact

AbstractNicotinamide adenine dinucleotide (NAD+) plays a critical role in energy metabolism and bioenergetic homeostasis. Most NAD+ in mammalian cells is synthesized via the NAD+ salvage pathway, where nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme, converting nicotinamide into nicotinamide mononucleotide (NMN). Using a Thy1-Nampt−/− projection neuron conditional knockout (cKO) mouse, we studied the impact of NAMPT on synaptic vesicle cycling in the neuromuscular junction (NMJ), end-plate structure of NMJs and muscle contractility of semitendinosus muscles. Loss of NAMPT impaired synaptic vesicle endocytosis/exocytosis in the NMJs. The cKO mice also had motor endplates with significantly reduced area and thickness. When the cKO mice were treated with NMN, vesicle endocytosis/exocytosis was improved and endplate morphology was restored. Electrical stimulation induced muscle contraction was significantly impacted in the cKO mice in a frequency dependent manner. The cKO mice were unresponsive to high frequency stimulation (100 Hz), while the NMN-treated cKO mice responded similarly to the control mice. Transmission electron microscopy (TEM) revealed sarcomere misalignment and changes to mitochondrial morphology in the cKO mice, with NMN treatment restoring sarcomere alignment but not mitochondrial morphology. This study demonstrates that neuronal NAMPT is important for pre-/post-synaptic NMJ function, and maintaining skeletal muscular function and structure.

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Memory in Salmon

Physiological Aspects of Imprinting and Homing Migration in Salmon - Advances in Environmental Engineering and Green Technologies ◽

10.4018/978-1-7998-2054-3.ch004 ◽

2020 ◽

pp. 76-93

Keyword(s):

Nervous System ◽

Synaptic Plasticity ◽

Sockeye Salmon ◽

Pacific Salmon ◽

Long Term Potentiation ◽

Memory Formation ◽

Olfactory Memory ◽

Aspartate Receptor ◽

Term Potentiation ◽

Chemical Synapses

It is unknown how salmon can imprint and retrieve information on their natal stream over a long period due to the lack of brain molecular markers for evaluating olfactory memory formation and retrieval. Memory in the brains of vertebrates is explained by the plasticity of the nervous system and the synaptic plasticity that promotes the ability of the chemical synapses to undergo changes in synaptic strength for long-term potentiation via the N-methyl-D-aspartate receptor, which has been identified a good molecular marker in the brain of salmon. This chapter describes the plasticity of the nervous system and synaptic plasticity, the involvement of the N-methyl-D-aspartate receptor in olfactory memory formation and retrieval in Pacific salmon, and functional magnetic resonance imaging of olfactory memory in lacustrine sockeye salmon.

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CAPS1 is involved in hippocampal synaptic plasticity and hippocampus-associated learning

Scientific Reports ◽

10.1038/s41598-021-88009-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chiaki Ishii ◽

Natsumi Shibano ◽

Mio Yamazaki ◽

Tomoki Arima ◽

Yuna Kato ◽

...

Keyword(s):

Synaptic Plasticity ◽

Long Term Potentiation ◽

Conditional Knockout ◽

Cellular Mechanisms ◽

Adeno Associated Virus ◽

Calcium Dependent ◽

Term Potentiation ◽

Hippocampal Ca3 ◽

Vesicular Exocytosis

AbstractCalcium-dependent activator protein for secretion 1 (CAPS1) is a key molecule in vesicular exocytosis, probably in the priming step. However, CAPS1’s role in synaptic plasticity and brain function is elusive. Herein, we showed that synaptic plasticity and learning behavior were impaired in forebrain and/or hippocampus-specific Caps1 conditional knockout (cKO) mice by means of molecular, physiological, and behavioral analyses. Neonatal Caps1 cKO mice showed a decrease in the number of docked vesicles in the hippocampal CA3 region, with no detectable changes in the distribution of other major exocytosis-related molecules. Additionally, long-term potentiation (LTP) was partially and severely impaired in the CA1 and CA3 regions, respectively. CA1 LTP was reinforced by repeated high-frequency stimuli, whereas CA3 LTP was completely abolished. Accordingly, hippocampus-associated learning was severely impaired in adeno-associated virus (AAV) infection-mediated postnatal Caps1 cKO mice. Collectively, our findings suggest that CAPS1 is a key protein involved in the cellular mechanisms underlying hippocampal synaptic release and plasticity, which is crucial for hippocampus-associated learning.

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Hippocampal synaptic plasticity: role in spatial learning or the automatic recording of attended experience?

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1997.0136 ◽

1997 ◽

Vol 352 (1360) ◽

pp. 1489-1503 ◽

Cited By ~ 218

Author(s):

R. G. M. Morris ◽

U. Frey

Keyword(s):

Synaptic Plasticity ◽

Nmda Receptor ◽

Spatial Learning ◽

Memory Task ◽

Learning Rule ◽

Nmda Antagonist ◽

Long Term Potentiation ◽

Reference Memory ◽

Automatic Recording ◽

Dependent Manner

Allocentric spatial learning can sometimes occur in one trial. The incorporation of information into a spatial representation may, therefore, obey a one–trial correlational learning rule rather than a multi–trial error–correcting rule. It has been suggested that physiological implementation of such a rule could be mediated by N –methyl–D–aspartate (NMDA) receptor–dependent long–term potentiation (LTP) in the hippocampus, as its induction obeys a correlational type of synaptic learning rule. Support for this idea came originally from the finding that intracerebral infusion of the NMDA antagonist AP5 impairs spatial learning, but studies summarized in the first part of this paper have called it into question. First, rats previously given experience of spatial learning in a watermaze can learn a new spatial reference memory task at a normal rate despite an appreciable NMDA receptor blockade. Second, the classical phenomenon of ‘blocking’ occurs in spatial learning. The latter finding implies that spatial learning can also be sensitive to an animal's expectations about reward and so depend on more than the detection of simple spatial correlations. In this paper a new hypothesis is proposed about the function of hippocampal LTP. This hypothesis retains the idea that LTP subserves rapid one–trial memory, but abandons the notion that it serves any specific role in the geometric aspects of spatial learning. It is suggested that LTP participates in the ‘automatic recording of attended experience’: a subsystem of episodic memory in which events are temporarily remembered in association with the contexts in which they occur. An automatic correlational form of synaptic plasticity is ideally suited to the online registration of context–event associations. In support, it is reported that the ability of rats to remember the most recent place they have visited in a familiar environment is exquisitely sensitive to AP5 in a delay–dependent manner. Moreover, new studies of the lasting persistence of NMDA–dependent LTP, known to require protein synthesis, point to intracellular mechanisms that enable transient synaptic changes to be stabilized if they occur in close temporal proximity to important events. This new property of hippocampal LTP is a desirable characteristic of an event memory system.

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Impairments of Long-Term Synaptic Plasticity in the Hippocampus of Young Rats during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

International Journal of Molecular Sciences ◽

10.3390/ijms222413355 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13355

Author(s):

Tatyana Y. Postnikova ◽

Georgy P. Diespirov ◽

Dmitry V. Amakhin ◽

Elizaveta N. Vylekzhanina ◽

Elena B. Soboleva ◽

...

Keyword(s):

Synaptic Plasticity ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Molecular Mechanisms ◽

Critical Role ◽

Long Term Potentiation ◽

Control Group ◽

High Frequency Stimulation ◽

Pilocarpine Model

Status epilepticus (SE) causes persistent abnormalities in the functioning of neuronal networks, often resulting in worsening epileptic seizures. Many details of cellular and molecular mechanisms of seizure-induced changes are still unknown. The lithium–pilocarpine model of epilepsy in rats reproduces many features of human temporal lobe epilepsy. In this work, using the lithium–pilocarpine model in three-week-old rats, we examined the morphological and electrophysiological changes in the hippocampus within a week following pilocarpine-induced seizures. We found that almost a third of the neurons in the hippocampus and dentate gyrus died on the first day, but this was not accompanied by impaired synaptic plasticity at that time. A diminished long-term potentiation (LTP) was observed following three days, and the negative effect of SE on plasticity increased one week later, being accompanied by astrogliosis. The attenuation of LTP was caused by the weakening of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling. NMDAR-current was more than two-fold weaker during high-frequency stimulation in the post-SE rats than in the control group. Application of glial transmitter D-serine, a coagonist of NMDARs, allows the enhancement of the NMDAR-dependent current and the restoration of LTP. These results suggest that the disorder of neuron–astrocyte interactions plays a critical role in the impairment of synaptic plasticity.

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Genomic benchmarking studies reveal variations of the polyubiquitination domain of the PSD95 protein in Homo neanderthalensis and other primates of the Hominidae family: Possible implications in cognitive functions?

Bionatura ◽

10.21931/rb/2021.06.01.23 ◽

2021 ◽

Vol 6 (1) ◽

pp. 1593-1601

Author(s):

Michael Zuarez-Chamba ◽

Luis Puma ◽

Jorge Bermeo ◽

Eugenio Andrade ◽

Stalin A. Bermúdez-Puga ◽

...

Keyword(s):

Synaptic Plasticity ◽

Critical Role ◽

Long Term Potentiation ◽

Primate Species ◽

Silent Mutation ◽

Nucleotide Position ◽

Last Common Ancestor ◽

Cognitive Evolution ◽

Modern Humans

Modern humans' unique cognitive abilities regarding Neanderthals and other primate's lineages are frequently attributed to the differences in brain size development and evolution. However, recent studies have established the critical role of genomic and genetic benchmarking in analyzing the cognitive evolution between modern humans and primates, focused mainly on searching for involved genes in neurogenesis. PSD95 protein (named PSD95p) has a key role in modulating synaptic plasticity, learning, and memory skills. Thus, the present study aimed to determine the possible variations of the PSD95 gene between modern humans, Neanderthals, and other hominid primate species using bioinformatics tools. The results showed 14 polymorphisms compared with the contemporary human PSD95 gene, of which 13 were silent mutations, and only one was a non-silent mutation at the nucleotide position 281. Despite polymorphisms found at the nucleotide sequences, the PSD95p of humans and chimpanzees are 100% identical. Likewise, the gorilla and orangutan PSD95p are 100% identical, although a 103-amino acid deletion characterizes them at the N-terminal end (1-103), suggesting that it behaves like a non-functional protein. Interestingly, the single nucleotide polymorphism (SNP) found at position 281 in the Neanderthal PSD95 gene leads to a change of the E94 to valine V94 in the polyubiquitination domain (PEST) and variation in the three-dimensional structure of PSD95 protein. We prompt that this structural change in the PEST domain could induce a loss of PSD95p function and, therefore, an alteration in synaptic plasticity forms such as long-term potentiation (LTP) and long-term depression (LTD). These findings open a possible hypothesis supporting the idea that humans' cognitive evolution after separating our last common ancestor with Neanderthals lineage could have been accompanied by discrete changes in the PSD95p polyubiquitination domain.

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Using Inspiration from Synaptic Plasticity Rules to Optimize Traffic Flow in Distributed Engineered Networks

Neural Computation ◽

10.1162/neco_a_00945 ◽

2017 ◽

Vol 29 (5) ◽

pp. 1204-1228 ◽

Cited By ~ 6

Author(s):

Jonathan Y. Suen ◽

Saket Navlakha

Keyword(s):

Synaptic Plasticity ◽

Traffic Flow ◽

Long Term Potentiation ◽

Network Activity ◽

Edge Weight ◽

Dependent Manner ◽

Gradient Descent Algorithm ◽

Update Rules ◽

The Brain

Controlling the flow and routing of data is a fundamental problem in many distributed networks, including transportation systems, integrated circuits, and the Internet. In the brain, synaptic plasticity rules have been discovered that regulate network activity in response to environmental inputs, which enable circuits to be stable yet flexible. Here, we develop a new neuro-inspired model for network flow control that depends only on modifying edge weights in an activity-dependent manner. We show how two fundamental plasticity rules, long-term potentiation and long-term depression, can be cast as a distributed gradient descent algorithm for regulating traffic flow in engineered networks. We then characterize, both by simulation and analytically, how different forms of edge-weight-update rules affect network routing efficiency and robustness. We find a close correspondence between certain classes of synaptic weight update rules derived experimentally in the brain and rules commonly used in engineering, suggesting common principles to both.

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