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.
Highlights
IntroductionSynaptic adhesion molecules mediate and regulate diverse aspects of synapse development and function (Dalva et al, 2007; Shen and Scheiffele, 2010; Siddiqui and Craig, 2011; Takahashi and Craig, 2013; Um and Ko, 2013; Ko et al, 2015; de Wit and Ghosh, 2016; Jang et al, 2017; Krueger-Burg et al, 2017; Südhof, 2017; Sudhof, 2018; Yuzaki, 2018; Kurshan and Shen, 2019; Ribic and Biederer, 2019)
N-methyl-Daspartate receptor (NMDAR)-miniature excitatory post-synaptic currents (mEPSCs), isolated by the AMPA receptors (AMPARs)/kainate receptors (KARs) antagonist NBQX, revealed a decrease in the frequency but not amplitude (Figure 3I). These results collectively suggest that Clmp deletion leads to changes in AMPAR, KAR, and NMDAR mEPSCs in Clmp−/− CA3 neurons; increased frequency and amplitude of AMPAR mEPSCs, increased frequency, amplitude, and decay time constant of KAR mEPSCs, and decreased frequency of NMDAR mEPSCs
Clmp expression reached a peak at around post-natal week 1 (Figure 2B), whereas IgSF11 expression steadily increases during post-natal brain development (Jang et al, 2016), and CAR expression reaches a peak around birth (Honda et al, 2000)
Summary
Synaptic adhesion molecules mediate and regulate diverse aspects of synapse development and function (Dalva et al, 2007; Shen and Scheiffele, 2010; Siddiqui and Craig, 2011; Takahashi and Craig, 2013; Um and Ko, 2013; Ko et al, 2015; de Wit and Ghosh, 2016; Jang et al, 2017; Krueger-Burg et al, 2017; Südhof, 2017; Sudhof, 2018; Yuzaki, 2018; Kurshan and Shen, 2019; Ribic and Biederer, 2019). Among the important synaptic proteins that are recruited to early synapses by synaptic adhesion molecules are post-synaptic neurotransmitter receptors. AMPARs and kainate receptors (KARs) are members of the ionotropic glutamate receptor (iGluR) family that act as ligandgated ion channels to mediate excitatory synaptic transmission and plasticity. Both receptor types are grouped together to form the non-NMDAR family (Mayer and Westbrook, 1987; Collingridge and Lester, 1989). Both AMPARs and KARs have been implicated in seizure pathophysiology and have been suggested as potential therapeutic targets (Rawls et al, 2009; Hibi et al, 2012; Kato et al, 2016; Falcon-Moya et al, 2018)
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