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

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Abstract

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.

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Acknowledgments

We thank Dr. Ann Marie Craig for her early guidance and vision. This work was supported by the National Natural Science Foundation of China (82001203, 82173819, 81871012, and 81571263), the Scientific Research Fund of Zhejiang Provincial Education Department (Y201839276), the Scientific Research Foundation of Zhejiang University City College (X-202103), the R&D Project of Zhejiang (2022C03034), the Natural Science Foundation of Zhejiang Province (LQ23C090001), and a Canada Research Chair Award (P2018-0246).

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  1. Xuehui Wang, Donghui Lin, and Jie Jiang contributed equally to this work.

Authors and Affiliations

  1. School of Life Sciences, Nanchang University, Nanchang, 330031, China

    Xuehui Wang, Yuhua Liu, Tonghui Xu & Yicheng Xie

  2. Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China

    Xuehui Wang, Donghui Lin, Jie Jiang, Yuhua Liu, Xinyan Dong, Lifen Gong, Kewen Jiang & Yicheng Xie

  3. Department of Biology, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada

    Jie Jiang & Steven A. Connor

  4. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310015, China

    Jianchen Fan, Weida Shen & Linghui Zeng

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  1. Xuehui Wang
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Correspondence to Kewen Jiang, Steven A. Connor or Yicheng Xie.

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Wang, X., Lin, D., Jiang, J. et al. MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity, Memory, and Social Behavior. Neurosci. Bull. (2024). https://doi.org/10.1007/s12264-023-01171-1

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