Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function

Steven A Connor; Ina Ammendrup-Johnsen; Yasushi Kishimoto; Parisa Karimi Tari; Vedrana Cvetkovska; Takashi Harada; Daiki Ojima; Tohru Yamamoto; Yu Tian Wang; Ann Marie Craig

doi:10.1016/j.celrep.2017.11.109

Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function

Cell Rep. 2017 Dec 26;21(13):3637-3645. doi: 10.1016/j.celrep.2017.11.109.

Affiliations

¹ Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Djavad Mowafaghian Centre for Brain Health and Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
² Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
³ Department of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa 769-2101, Japan.
⁴ Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan.
⁵ Djavad Mowafaghian Centre for Brain Health and Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
⁶ Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: acraig@mail.ubc.ca.

PMID: 29281813
DOI: 10.1016/j.celrep.2017.11.109

Abstract

Synaptopathies contributing to neurodevelopmental disorders are linked to mutations in synaptic organizing molecules, including postsynaptic neuroligins, presynaptic neurexins, and MDGAs, which regulate their interaction. The role of MDGA1 in suppressing inhibitory versus excitatory synapses is controversial based on in vitro studies. We show that genetic deletion of MDGA1 in vivo elevates hippocampal CA1 inhibitory, but not excitatory, synapse density and transmission. Furthermore, MDGA1 is selectively expressed by pyramidal neurons and regulates perisomatic, but not distal dendritic, inhibitory synapses. Mdga1^-/- hippocampal networks demonstrate muted responses to neural excitation, and Mdga1^-/- mice are resistant to induced seizures. Mdga1^-/- mice further demonstrate compromised hippocampal long-term potentiation, consistent with observed deficits in spatial and context-dependent learning and memory. These results suggest that mutations in MDGA1 may contribute to cognitive deficits through altered synaptic transmission and plasticity by loss of suppression of inhibitory synapse development in a subcellular domain- and cell-type-selective manner.

Keywords: E/I ratio; Neuroligin; hippocampus; inhibitory synapse; memory; neurexin; neurodevelopmental disorders; synapse development; synaptic plasticity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CA1 Region, Hippocampal / pathology
Cognition*
Gene Deletion
Long-Term Potentiation
Mice, Inbred C57BL
Mice, Knockout
Nerve Net / metabolism*
Neural Cell Adhesion Molecules / deficiency
Neural Cell Adhesion Molecules / metabolism*
Neural Inhibition*
Synapses / metabolism*
Synapses / ultrastructure
Synaptic Transmission

Substances

Mdga1 protein, mouse
Neural Cell Adhesion Molecules

Grants and funding

FDN 143206/CIHR/Canada