MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity,Memory,and Social Behavior

Synapse organizers are essential for the development,transmission,and plasticity of synapses.Acting as rare synapse suppressors,the MAM domain containing glycosylphosphatidylinositol anchor(MDGA)proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex.A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with autism.However,MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory synapses.Differentiating the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective strategy.To address this,we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal neurons.Here we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature hippocampus.Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials,vesicular glutamate transporter 1 intensity,and neuronal excitability.These effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter intensity.Functionally,evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic inputs.At a behavioral level,memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired,consistent with deficits in long-term potentiation in the CA3-CA1 pathway.Social affiliation,a behavioral analog of social deficits in autism,was similarly compromised.These results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits,thereby optimizing this network for plasticity,cognition,and social behaviors.

嗜粘蛋白阿克曼菌在糖尿病和肥胖中的作用

肠道微生物在平衡健康与疾病的过程中起着重要作用。嗜粘蛋白阿克曼菌(Akkermansia muciniphila)是肠道微生物中的一种,其在降解肠道粘蛋白方面的特性使其成为肠腔与宿主细胞黏膜界面的关键生物。嗜粘蛋白阿克曼菌与肥胖、糖尿病、心血管代谢疾病和低度炎症呈负相关。口服嗜粘蛋白阿克曼菌可改善小鼠代谢疾病的相关症状,嗜粘蛋白阿克曼菌有望成为治疗2型糖尿病和肥胖的候选药物。本综述通过总结现有关于嗜粘蛋白阿克曼菌在糖尿病和肥胖症中发挥作用的研究,指出嗜粘蛋白阿克曼菌调节宿主和肠道微生物群之间相互作用可能存在的机制,为嗜粘蛋白阿克曼菌的进一步研究和糖尿病的新药研发提供思路。