The Mechanism Of Menin Regulating Parvalbumin Neuron Function In The Pathogenesis Of Depression

Depression is a major nervous system disease with great harm,high heterogeneity and easy recurrence.It is closely related to genetic and environmental factors.So far,the pathogenesis of depression involves a wide range of mechanisms,such as abnormal HPA axis hormone secretion,disordered various neurotransmitter signaling,occurrence of inflammation,and alteration in synaptic plasticity.Among these mechanisms,dysfunction of inhibitory neurons in the brain is an important factor in depression.γ-aminobutyric acid(GABA)ergic interneurons in the brain mainly contain four types:Parvalbumin(PV),Somatostatin(SST),Vasoactive intestinal peptide(VIP)and Reelin(RELN)positive interneurons.Interneurons in the cortex account for 20%of the cortical neurons,These four categories account for 40%,30%,15%and 15%of interneurons,respectively.PV+neurons are the largest group of interneurons,and their dysfunctions are often reported in autism,schizophrenia,depression and other psychiatric diseases,but their specific functions in the diseases are still unknown.In order to further study the function of PV+ neurons,we started from the neuroendocrine regulation that closely related to depression.We found that multiple endocrine neoplasia factor 1(MEN1)played an important role in the pathogenesis of depression and the regulation of PV.MEN1 is an endocrine tumor suppressor gene,its encoding Menin is widely expressed in the nervous system,but its function is poorly understood.Our laboratory previous discovered that mice showed depression-like behaviors after knockout Menin in the central nervous system,as well as increased GABA concentration,and significantly decreased the protein and mRNA levels of GAT1(GABA transporter 1).We found that the absence of Menin in the whole interneurons also led to the depressive-like phenotypes in mice.Moreover,the knockout mice showed increased number of interneurons,which was especially reflected in the number of PV positive interneurons.Further,we constructed PV+interneuron knockout Menin mice that similarly exhibited depressive behaviors and increased number of PV+interneurons.GAT1 overexpression virus can increase GABA intake and rescue the depression phenotype of knockout mice.In summary,our results indicated that the absence of Menin increases the number of PV neurons,leading to increased GAB A secretion and amplified GAB A signal transmission,which led to depressive behaviors in mice.Overexpression of GAT1 can increase the recycling GABA,and can alleviate the phenotype of knockout mice.These discoveries provide a new clue for the mechanism of depression and provide a new target for drug development.