Defective synapse maturation and enhanced synaptic plasticity in Shank2-/- mice

SummaryAutism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic aetiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are employed for a mechanistic understanding of ASDs and the development of therapeutic strategies. In sharp contrast to all studies so far on the function of SHANK proteins, we observe enhanced synaptic plasticity in Shank2-/- mice, under various conditions in vitro and in vivo. Reproducing and extending previous results, we here present a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation (LTP) by describing a synaptic maturation deficit in Shank2-/- mice.

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Brivaracetam Prevents the Over-expression of Synaptic Vesicle Protein 2A and Rescues the Deficits of Hippocampal Long-term Potentiation In Vivo in Chronic Temporal Lobe Epilepsy Rats

Current Neurovascular Research ◽

10.2174/1567202617666200514114917 ◽

2020 ◽

Vol 17 (4) ◽

pp. 354-360 ◽

Cited By ~ 1

Author(s):

Yu-Xing Ge ◽

Ying-Ying Lin ◽

Qian-Qian Bi ◽

Yu-Juan Chen

Keyword(s):

Synaptic Plasticity ◽

Temporal Lobe Epilepsy ◽

Synaptic Vesicle ◽

Long Term Potentiation ◽

Synaptic Dysfunction ◽

Over Expression ◽

Term Potentiation ◽

Synaptic Vesicle Protein 2A

Background: Patients with temporal lobe epilepsy (TLE) usually suffer from cognitive deficits and recurrent seizures. Brivaracetam (BRV) is a novel anti-epileptic drug (AEDs) recently used for the treatment of partial seizures with or without secondary generalization. Different from other AEDs, BRV has some favorable properties on synaptic plasticity. However, the underlying mechanisms remain elusive. Objective: The aim of this study was to explore the neuroprotective mechanism of BRV on synaptic plasticity in experimental TLE rats. Methods: The effect of chronic treatment with BRV (10 mg/kg) was assessed on Pilocarpine induced TLE model through measurement of the field excitatory postsynaptic potentials (fEPSPs) in vivo. Differentially expressed synaptic vesicle protein 2A (SV2A) were identified with immunoblot. Then, fast phosphorylation of synaptosomal-associated protein 25 (SNAP-25) during long-term potentiation (LTP) induction was performed to investigate the potential roles of BRV on synaptic plasticity in the TLE model. Results: An increased level of SV2A accompanied by a depressed LTP in the hippocampus was shown in epileptic rats. Furthermore, BRV treatment continued for more than 30 days improved the over-expression of SV2A and reversed the synaptic dysfunction in epileptic rats. Additionally, BRV treatment alleviates the abnormal SNAP-25 phosphorylation at Ser187 during LTP induction in epileptic ones, which is relevant to the modulation of synaptic vesicles exocytosis and voltagegated calcium channels. Conclusion: BRV treatment ameliorated the over-expression of SV2A in the hippocampus and rescued the synaptic dysfunction in epileptic rats. These results identify the neuroprotective effect of BRV on TLE model.

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Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

The Journal of Cell Biology ◽

10.1083/jcb.201501114 ◽

2015 ◽

Vol 210 (5) ◽

pp. 771-783 ◽

Cited By ~ 8

Author(s):

Norbert Bencsik ◽

Zsófia Szíber ◽

Hanna Liliom ◽

Krisztián Tárnok ◽

Sándor Borbély ◽

...

Keyword(s):

Synaptic Plasticity ◽

Protein Kinase ◽

Dendritic Spines ◽

Morphological Changes ◽

Long Term Potentiation ◽

Memory Formation ◽

Protein Kinase D

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

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P4-378: REVERSAL OF AB-INDUCED DEFICITS IN LONG-TERM POTENTIATION (LTP) IN VITRO AND IN VIVO BY MRZ-99030

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.07.147 ◽

2014 ◽

Vol 10 ◽

pp. P926-P926

Author(s):

Christopher G. Parsons ◽

Ross David Jeggo ◽

Lydia Staniaszek ◽

David Spanswick ◽

Gerhard Rammes

Keyword(s):

Long Term Potentiation ◽

Term Potentiation

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Nicotine Enhances the Depressive Actions of Aβ1–40 on Long-Term Potentiation in the Rat Hippocampal CA1 Region In Vivo

Journal of Neurophysiology ◽

10.1152/jn.00996.2002 ◽

2003 ◽

Vol 89 (6) ◽

pp. 2917-2922 ◽

Cited By ~ 35

Author(s):

D. B. Freir ◽

C. E. Herron

Keyword(s):

Synaptic Plasticity ◽

Long Term Potentiation ◽

Α7 Nicotinic Acetylcholine Receptor ◽

High Affinity ◽

Ca1 Region ◽

Α7 Nachr ◽

Term Potentiation ◽

Significant Depression

Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (Aβ) is involved in Alzheimer's disease (AD), a neurode-generative disorder leading to cognitive deficits. Nicotine is also claimed to act as a cognitive enhancer. Aβ is known to bind with high affinity to the α7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (icv) injection of the endogenous peptide Aβ1–40 on LTP in area CA1 of urethananesthetized rats. We also examined the effect of Aβ12–28 (icv), which binds with high affinity to the α7-nAChR and the specific α7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that Aβ12–28 had no effect on LTP, whereas MLA depressed significantly LTP, suggesting that activation of the α7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with Aβ12–28 for binding to α7-nAChR, it does not appear to modulate LTP. To determine if the depressive action of Aβ1–40 on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10 nmol Aβ1–40 caused a significant depression of LTP, whereas nicotine alone (3 mg/kg) had no effect on LTP. Co-injection of nicotine with Aβ1–40 1 h prior to LTP induction caused a further significant depression of LTP compared with Aβ1–40 alone. These results demonstrate that nicotine enhances the deficit in LTP produced by Aβ1–40. This then suggests that nicotine may exacerbate the depressive actions of Aβ on synaptic plasticity in AD.

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Widespread promoter methylation of synaptic plasticity genes in long-term potentiation in the adult brain in vivo

BMC Genomics ◽

10.1186/s12864-017-3621-x ◽

2017 ◽

Vol 18 (1) ◽

Cited By ~ 14

Author(s):

Jesper L. V. Maag ◽

Dominik C. Kaczorowski ◽

Debabrata Panja ◽

Timothy J. Peters ◽

Clive R. Bramham ◽

...

Keyword(s):

Synaptic Plasticity ◽

Promoter Methylation ◽

Long Term Potentiation ◽

Adult Brain ◽

Term Potentiation

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Neuroligin-3 Regulates Excitatory Synaptic Transmission and EPSP-Spike Coupling in the Dentate Gyrus In Vivo

Molecular Neurobiology ◽

10.1007/s12035-021-02663-9 ◽

2021 ◽

Author(s):

Julia Muellerleile ◽

Matej Vnencak ◽

Angelo Ippolito ◽

Dilja Krueger-Burg ◽

Tassilo Jungenitz ◽

...

Keyword(s):

Synaptic Transmission ◽

Dentate Gyrus ◽

Long Term Potentiation ◽

Autism Spectrum ◽

Perforant Path ◽

Adhesion Protein ◽

Neuronal Excitation ◽

Term Potentiation

Abstract Neuroligin-3 (Nlgn3), a neuronal adhesion protein implicated in autism spectrum disorder (ASD), is expressed at excitatory and inhibitory postsynapses and hence may regulate neuronal excitation/inhibition balance. To test this hypothesis, we recorded field excitatory postsynaptic potentials (fEPSPs) in the dentate gyrus of Nlgn3 knockout (KO) and wild-type mice. Synaptic transmission evoked by perforant path stimulation was reduced in KO mice, but coupling of the fEPSP to the population spike was increased, suggesting a compensatory change in granule cell excitability. These findings closely resemble those in neuroligin-1 (Nlgn1) KO mice and could be partially explained by the reduction in Nlgn1 levels we observed in hippocampal synaptosomes from Nlgn3 KO mice. However, unlike Nlgn1, Nlgn3 is not necessary for long-term potentiation. We conclude that while Nlgn1 and Nlgn3 have distinct functions, both are required for intact synaptic transmission in the mouse dentate gyrus. Our results indicate that interactions between neuroligins may play an important role in regulating synaptic transmission and that ASD-related neuroligin mutations may also affect the synaptic availability of other neuroligins.

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Simvastatin Impairs Hippocampal Synaptic Plasticity and Cognitive Function in Mice

10.21203/rs.3.rs-76680/v2 ◽

2021 ◽

Author(s):

Yujun Guo ◽

Guichang Zou ◽

Keke Qi ◽

Jin Jin ◽

Lei Yao ◽

...

Keyword(s):

Synaptic Plasticity ◽

Memory Function ◽

Long Term Potentiation ◽

Drug Discontinuation ◽

Cholesterol Levels ◽

Hippocampal Synaptic Plasticity ◽

Term Potentiation ◽

The Central Nervous System

Abstract Lipophilic statins which are blood brain barrier (BBB) permeable are speculated to affect the cholesterol synthesis and neural functions in the central nervous system. However, whether these statins can affect cholesterol levels and synaptic plasticity in hippocampus and the in vivo consequence remain unclear. Here, we report that long-term subcutaneous treatments of simvastatin significantly impair mouse hippocampal synaptic plasticity, reflected by the attenuated long-term potentiation of field excitatory postsynaptic potentials. The simvastatin administration causes a deficiency in recognition and spatial memory but fails to affect motor ability and anxiety behaviors in the mice. Mass spectrometry imaging indicates a significant decrease in cholesterol intensity in hippocampus of the mice receiving chronic simvastatin treatments. Such effects of simvastatin are transient because drug discontinuation can restore the hippocampal cholesterol level and synaptic plasticity and the memory function. These findings may provide further clues to elucidate the mechanisms of neurological side effects, especially the brain cognitive

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Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors

Cell Death and Disease ◽

10.1038/s41419-020-03051-2 ◽

2020 ◽

Vol 11 (10) ◽

Cited By ~ 1

Author(s):

Zhuo Ma ◽

Kuan Liu ◽

Xin-Ru Li ◽

Can Wang ◽

Chang Liu ◽

...

Keyword(s):

Synaptic Plasticity ◽

Spatial Memory ◽

Long Term Potentiation ◽

Alpha Synuclein ◽

Ht22 Cells ◽

Protein Levels ◽

Trkb Receptors ◽

Term Potentiation

Abstract Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (α-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and α-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and synaptic plasticity were related to the α-Syn protein. In addition, consistent with the long-term potentiation (LTP) impairments that were observed, α-Syn KO relieved Mn-induced degradation of PSD95, phosphorylated CaMKIIα, and downregulated SynGAP protein levels. We transfected HT22 cells with lentivirus (LV)-α-Syn shRNA, followed by BDNF and Mn stimulation. In vitro experiments indicated that α-Syn selectively interacted with TrkB receptors and inhibited BDNF/TrkB signaling, leading to phosphorylation and downregulation of GluN2B. The binding of α-Syn to TrkB and Fyn-mediated phosphorylation of GluN2B were negatively regulated by BDNF. Together, these findings indicate that Mn-dependent enhanced α-Syn expression contributes to further exacerbate BDNF protein-level reduction and to inhibit TrkB/Akt/Fyn signaling, thereby disturbing Fyn-mediated phosphorylation of the NMDA receptor GluN2B subunit at tyrosine. In KO α-Syn mice treated with Mn, spatial memory and LTP impairments were less pronounced than in WT mice. However, the same robust neuronal death was observed as a result of Mn-induced neurotoxicity.

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