The Critical Time Window Of Excitatory Synapse Formation In PV-positive GABAergic Interneurons And Its Regulation By NMDA Receptor

Parvalbumin（PV）positive inhibitory interneurons play an important role in regulating the excitation/inhibition balance of the cerebral cortex.The abnormal development or dysfunction of PV interneurons is closely related to the occurrence of mental diseases such as schizophrenia,autism,and intellectual impairment.Excitatory synapses were reduced in the PFC of patients with schizophrenia.At present,the key period and internal molecular mechanism of excitatory synaptic development of PV interneurons have not been fully studied.In this study,immunofluorescence staining and three-dimensional reconstruction through Vaa3 D were used to study the excitatory synapse development of PV interneurons in PFC.We found that 4-6 week was the critical period of excitatory synapse pruning,and 6-8 week was the critical period of excitatory synapse maturation.To explore the molecular mechanism of excitatory synapse development of PV interneurons,we analyzed the different expression genes in cortical PV interneurons of adolescent and adult mouse by mining single-cell sequencing data.It was found that Grin2 b was the key gene regulating the excitatory synapse development of PV interneurons.Grin2 b encodes Glu N2 B,a subunit of NMDA receptor,playing an important role in synaptic plasticity,learning,and memory.We injected NMDA receptor antagonist MK801 intraperitoneally into adolescent（3-5 weeks after birth）mouse once a day（14 days total）,and analyzed the density and size of excitatory synapses of PV interneurons in PFC.The main results are as follows: 1)It has no significant effect on brain weight and body weight of mouse;2)The density of PV interneurons in PFC was not affected;3)Affect the formation of excitatory synapses of PV interneurons rather than pruning,and reduce the density and size of excitatory synapses of PV interneurons;4)Mouse showed hyperactive behavioral characteristics.In conclusion,our study revealed the key time window of excitatory synaptic development of PV interneurons and NMDA receptor plays an important role.Considering that the decline of NMDA receptor function is one of the hypotheses of the pathogenesis of schizophrenia,this study also provides new clues for the pathogenesis of schizophrenia.