Dataset Information

Clmp Regulates AMPA and Kainate Receptor Responses in the Neonatal Hippocampal CA3 and Kainate Seizure Susceptibility in Mice.

ABSTRACT: Synaptic adhesion molecules regulate synapse development through trans-synaptic adhesion and assembly of diverse synaptic proteins. Many synaptic adhesion molecules positively regulate synapse development; some, however, exert negative regulation, although such cases are relatively rare. In addition, synaptic adhesion molecules regulate the amplitude of post-synaptic receptor responses, but whether adhesion molecules can regulate the kinetic properties of post-synaptic receptors remains unclear. Here we report that Clmp, a homophilic adhesion molecule of the Ig domain superfamily that is abundantly expressed in the brain, reaches peak expression at a neonatal stage (week 1) and associates with subunits of AMPA receptors (AMPARs) and kainate receptors (KARs). Clmp deletion in mice increased the frequency and amplitude of AMPAR-mediated miniature excitatory post-synaptic currents (mEPSCs) and the frequency, amplitude, and decay time constant of KAR-mediated mEPSCs in hippocampal CA3 neurons. Clmp deletion had minimal impacts on evoked excitatory synaptic currents at mossy fiber-CA3 synapses but increased extrasynaptic KAR, but not AMPAR, currents, suggesting that Clmp distinctly inhibits AMPAR and KAR responses. Behaviorally, Clmp deletion enhanced novel object recognition and susceptibility to kainate-induced seizures, without affecting contextual or auditory cued fear conditioning or pattern completion-based contextual fear conditioning. These results suggest that Clmp negatively regulates hippocampal excitatory synapse development and AMPAR and KAR responses in the neonatal hippocampal CA3 as well as object recognition and kainate seizure susceptibility in mice.

SUBMITTER: Jang S

PROVIDER: S-EPMC7779639 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Clmp Regulates AMPA and Kainate Receptor Responses in the Neonatal Hippocampal CA3 and Kainate Seizure Susceptibility in Mice.

Jang Seil S Yang Esther E Kim Doyoun D Kim Hyun H Kim Eunjoon E

Frontiers in Synaptic Neuroscience 20201221

Synaptic adhesion molecules regulate synapse development through trans-synaptic adhesion and assembly of diverse synaptic proteins. Many synaptic adhesion molecules positively regulate synapse development; some, however, exert negative regulation, although such cases are relatively rare. In addition, synaptic adhesion molecules regulate the amplitude of post-synaptic receptor responses, but whether adhesion molecules can regulate the kinetic properties of post-synaptic receptors remains unclear. ...[more]

PMID: 33408624

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Project description:Epilepsy is one of the most prevalent and drug-refractory neurological disorders. Zinc finger DHHC-type containing 8 (ZDHHC8) is a putative palmitoyltransferase that is highly expressed in the brain. However, the impact of ZDHHC8 on seizures remains unclear. We aimed to explore the association of ZDHHC8 with epilepsy and investigate its in epileptogenesis in in vivo and in vitro models through behavioral, electrophysiological, and pathological studies. We used kainic acid- and pilocarpine-induced C57BL/6 mice and magnesium-free-induced pyramidal neurons as experimental epileptic models in this study. We first found increased ZDHHC8 expression in the brains of temporal lobe epilepsy (TLE) patients, similar to that observed in chronic epileptic mice, strongly suggesting that ZDHHC8 is correlated with human epilepsy. In the in vitro seizure models, knocking down ZDHHC8 using recombinant adeno-associated virus (rAAV) delayed seizure precipitation and decreased chronic spontaneous recurrent seizures (SRSs) and epileptiform-like discharges, while ZDHHC8 overexpression had the opposite effect. ZDHHC8 levels were consistent with seizure susceptibility in induced mice with SRSs. In an in vitro magnesium-free model, neuronal hyperexcitability and hypersynchrony were reduced in ZDHHC8-knockdown neurons but were increased in ZDHHC8-overexpressing neurons. To further explore the potential mechanisms, we observed that ZDHHC8 had a significant modulatory effect on 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor-related excitatory, but not inhibitory, glutamatergic synaptic neurotransmission, further affecting the inward rectification of AMPA currents in acute hippocampal slices in whole-cell recordings. ZDHHC8 facilitated GluA1 trafficking to the neuronal surface in the hippocampus, as shown by immunoprecipitation and Western blotting. These results suggest that ZDHHC8 may promote the generation and propagation of seizures in humans and that knocking down ZDHHC8 might produce anti-epileptogenic effects in drug-resistant epilepsy. Our study provides evidence that may facilitate the development of an alternative approach for the treatment of epilepsy by modulating AMPA/GluA1-mediated neurotransmission.

Project description:Background Pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) selectively dephosphorylates serine (S) 10 site on neurofibromin 2 (NF2, also known as merlin (moesin-ezrin-radixin-like protein) or schwannomin). p21-activated kinase 1 (PAK1) is a serine/threonine protein kinase, which is involved in synaptic activity and plasticity in neurons. NF2 and PAK1 reciprocally regulate each other in a positive feedback manner. Thus, the aim of the present study is to investigate the effects of PLPP/CIN-mediated NF2 S10 dephosphorylation on PAK1-related signaling pathways under physiological and neuroinflammatory conditions, which are largely unknown. Methods After kainate (KA) injection in wild-type, PLPP/CIN−/− and PLPP/CINTg mice, seizure susceptibility, PAK1 S204 autophosphorylation, nuclear factor-κB (NF-κB) p65 S276 phosphorylation, cyclooxygenase-2 (COX-2) upregulation, prostaglandin E synthase 2 (PTGES2) induction and neuronal damage were measured. The effects of 1,1'-dithiodi-2-naphthtol (IPA-3, a selective inhibitor of PAK1) pretreatment on these responses to KA were also validated. Results PLPP/CIN overexpression increased PAK1 S204 autophosphorylation concomitant with the enhanced NF2 S10 dephosphorylation in hippocampal neurons under physiological condition. Following KA treatment, PLPP/CIN overexpression delayed the seizure on-set and accelerated PAK1 S204 phosphorylation, NF-κB p65 S276 phosphorylation, COX-2 upregulation and PTGES2 induction, which were ameliorated by PLPP/CIN deletion or IPA-3. Furthermore, IPA-3 pretreatment shortened the latency of seizure on-set without affecting seizure severity (intensity) and ameliorated CA3 neuronal death induced by KA. Conclusions These findings indicate that PLPP/CIN may regulate seizure susceptibility (the latency of seizure on-set) and CA3 neuronal death in response to KA through NF2-PAK1-NF-κB-COX-2-PTGES2 signaling pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-023-02788-9.

Dataset Information

Clmp Regulates AMPA and Kainate Receptor Responses in the Neonatal Hippocampal CA3 and Kainate Seizure Susceptibility in Mice.

Publications

Clmp Regulates AMPA and Kainate Receptor Responses in the Neonatal Hippocampal CA3 and Kainate Seizure Susceptibility in Mice.

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