Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Synaptotagmin-7 (Syt7) is implicated in bipolar-like behaviors, but mechanisms are unclear.
• N-methyl-D-aspartate receptor (NMDAR)-targeted drugs have moderate efficacy in bipolar disorder, with overcorrection being a concern.

Purpose of the Study:

• Investigate the role of Syt7 in bipolar disorder pathophysiology.
• Elucidate the mechanism linking Syt7, NMDARs, and mood regulation.
• Explore Syt7's influence on NMDAR antagonist efficacy.

Main Methods:

• Identified Syt7 single nucleotide polymorphisms (SNPs) in bipolar disorder patients.
• Generated and analyzed Syt7 knockout and SNP-expressing mice.
• Utilized human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons.
• Assessed GluN2B-NMDAR function and glutamate release.

Main Results:

• Syt7 deficiency or SNPs in mice led to GluN2B-NMDAR dysfunction and antidepressant-like behaviors.
• Syt7 and GluN2B-NMDARs colocalize at the synaptic periphery, with Syt7 modulating glutamate release.
• Patient iPSC-derived neurons with Syt7 deficits showed reduced GluN2B-NMDAR activity, rescued by Syt7.
• Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity.

Conclusions:

• Syt7 deficits impair GluN2B-NMDAR function, contributing to bipolar-like behaviors.
• This impairment explains the avoidance of mood overcorrection by NMDAR antagonists.
• Syt7 is a potential therapeutic target for bipolar disorder.