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Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression
Woosuk Chung1, Su Yeon Choi2, Eunee Lee3
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Abstract:
Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53(-/-) mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects.
Insights
Mice lacking IRSp53 showed social deficits due to altered NMDA receptor (NMDAR) function. Memantine or MPEP treatment normalized social behavior by restoring NMDAR function, suggesting NMDAR balance is crucial for social interaction.
Area of Science:
- Neuroscience
- Psychiatric Disorders
- Synaptic Plasticity
Background:
- Social deficits are common in psychiatric disorders like autism and schizophrenia.
- The excitatory synaptic signaling scaffold IRSp53 (BAIAP2) plays a role in neuronal function.
- Altered NMDA receptor (NMDAR) function is implicated in social impairments.
Purpose of the Study:
- To investigate the role of IRSp53 in social behavior.
- To explore the link between NMDAR function and social deficits.
- To determine if modulating NMDAR function can rescue social impairments.
Main Methods:
- Studied mice lacking the IRSp53 gene (IRSp53(-/-)).
- Administered NMDAR antagonist memantine and mGluR5 antagonist MPEP to IRSp53(-/-) mice.
- Assessed social interaction, NMDAR function, synaptic plasticity, and neuronal firing.
Main Results:
- IRSp53(-/-) mice exhibited impaired social interaction and communication.
- These mice showed enhanced hippocampal NMDAR function.
- Treatment with memantine or MPEP normalized social behavior, hippocampal NMDAR function, plasticity, and medial prefrontal cortex neuronal firing.
Conclusions:
- Deviation in NMDAR function, either enhanced or reduced, contributes to social deficits.
- Restoring NMDAR function towards normal levels can ameliorate social impairments.
- IRSp53 deficiency-induced social deficits are linked to aberrant NMDAR activity.
