Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior.

Sthitapranjya Pati,Pratik R Chaudhari,Darshana Kapri,James P Clement,Sonali S Salvi,Anant B Patel,Shital Suryavanshi,Vijaya Verma,Praachi Tiwari,Sourish Mukhopadhyay,Vidita A Vaidya,Kamal Saba

doi:10.7554/elife.56171

Abstract

Early adversity is a risk factor for the development of adult psychopathology. Common across multiple rodent models of early adversity is increased signaling via forebrain Gq-coupled neurotransmitter receptors. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke persistent mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of forebrain excitatory neurons during postnatal life (P2-14), but not in juvenile or adult windows, increased anxiety-, despair-, and schizophrenia-like behavior in adulthood. This was accompanied by an enhanced metabolic rate of cortical and hippocampal glutamatergic and GABAergic neurons. Furthermore, we observed reduced activity and plasticity-associated marker expression, and perturbed excitatory/inhibitory currents in the hippocampus. These results indicate that Gq-signaling-mediated activation of forebrain excitatory neurons during the critical postnatal window is sufficient to program altered mood-related behavior, as well as functional changes in forebrain glutamate and GABA systems, recapitulating aspects of the consequences of early adversity.

Highlights

Life experience plays a crucial role in the maturation and fine-tuning of neurocircuitry that drives emotional behavior in adulthood[1,2,3,4,5,6]
The major finding of our study is that chronic chemogenetic hM3Dq Designer Receptors Exclusively Activated by Designer Drugs (DREADD) activation of CamKIIα-positive forebrain excitatory neurons in the first two weeks of postnatal life is sufficient to program the emergence of enhanced anxiety, despair- and schizophrenialike behavior in adult male mice
Chronic chemogenetic activation of CamKIIαpositive forebrain excitatory neurons in either the juvenile or adult temporal window did not result in any persistent changes in mood-related behavior

Summary

Introduction

Life experience plays a crucial role in the maturation and fine-tuning of neurocircuitry that drives emotional behavior in adulthood[1,2,3,4,5,6]. Both clinical and preclinical evidence indicates that early life adversity serves as a key risk factor for the development of adult psychopathology, increasing susceptibility to psychiatric disorders like anxiety, major depression and schizophrenia[5,7,8,9,10]. Amongst the underlying mechanisms implicated in the establishment of such long-lasting changes in response to early life perturbations are a dysregulation of the hormonal stress response pathway[22,26,27,28,29,30], serotonergic system[31,32,33], and emergence of excitation-inhibition balance within key cortical neurocircuits[34,35]

Methods

Results

Conclusion