Jiang Yan's team analyzed the molecular mechanism regulating the development of cortical Htr3a interneurons and its impact on emotional behavior

GABAergic interneurons in the cerebral cortex originate from the ganglion bulge in the embryonic stage, migrate to the cortex during development, accounting for 20%-30% of the total number of neurons in the adult cortex, which is essential
for maintaining the excitatory and inhibitory balance of the cortical neural network.
Dysfunction of cortical interneurons is thought to be a potential pathogenesis
of a variety of psychiatric disorders.
The latest research team of Jiang Yan, Institute of Brain Sciences/State Key Laboratory of Medical Neurobiology, Fudan University, found that the histone methyltransferase SETDB1 can specifically affect the gene expression of Htr3a in interneurons, and deeply analyzed its intrinsic epigenetic regulation mechanism
.
It was further found that the dysregulation of Htr3a gene expression had an important impact on
the development, electrophysiological characteristics and emotional behavior of Htr3a-positive interneuron subsets in the cortex 。 The study, titled "Histone methyltransferase SETDB1 regulates the development of cortical Htr3a positive interneurons and mood behaviors," was published in the journal Biological Psychiatry in 2022
.

Htr3a is thought to mark most of the interneurons originating from the caudal ganglion bulge, encoding the A subunit of serotonin receptor 3, and its abnormal expression has been found to be closely related
to emotional behavior disorders in clinical studies and various mouse stress models 。 Jiang Yan's team applied RNA-seq, ATAC-seq, ChIP-seq, Luciferase reporting system, Chromatin Conformation Capture (3C), and CRISPR/dCas9 technology to find that the H3K9me3-specific methyltransferase SETDB1 inhibits the enhancer activity of RMER21B elements in cortical interneurons of the GABA energy lineage.
Specifically regulate the gene expression of Htr3a in the form of remote chromatin loops; Furthermore, through in situ hybridization, electrophysiology and behavior, it was found that the increase of Htr3a expression can promote the development of this specific interneuron subset, change the excitability of cortical neurons in adulthood, and lead to abnormal
emotional behavior.
The results of this study provide a new theoretical basis
for Htr3a as a potential target for the treatment of affective disorders.

The study was completed under the guidance of corresponding author Jiang Yan, with Li Jiaqi, a direct doctoral student and Zheng Shenghui, a doctoral student at the Institute of Brain Science, Fudan University, as the co-first authors of the paper, and supported
by Xiao Lei's research group of the Institute of Brain Science.
This research was supported
by the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Commission and the Shanghai Science and Technology Major Project.