Abstract
G-protein-coupled receptors (GPCRs) coupled to Gi signaling, in particular downstream of monoaminergic neurotransmission, are posited to play a key role during developmental epochs (postnatal and juvenile) in shaping the emergence of adult anxiodepressive behaviors and sensorimotor gating. To address the role of Gi signaling in these developmental windows, we used a CaMKIIα-tTA::TRE hM4Di bigenic mouse line to express the hM4Di-DREADD (designer receptor exclusively activated by designer drugs) in forebrain excitatory neurons and enhanced Gi signaling via chronic administration of the DREADD agonist, clozapine-N-oxide (CNO) in the postnatal window (postnatal days 2–14) or the juvenile window (postnatal days 28–40). We confirmed that the expression of the HA-tagged hM4Di-DREADD was restricted to CaMKII-positive neurons in the forebrain, and that the administration of CNO in postnatal or juvenile windows evoked inhibition in forebrain circuits of the hippocampus and cortex, as indicated by a decline in expression of the neuronal activity marker c-fos. hM4Di-DREADD-mediated inhibition of CaMKIIα-positive forebrain excitatory neurons in postnatal or juvenile life did not impact the weight profile of mouse pups, and also did not influence the normal ontogeny of sensory reflexes. Further, postnatal or juvenile hM4Di-DREADD-mediated inhibition of CaMKIIα-positive forebrain excitatory neurons did not alter anxiety- or despair-like behaviors in adulthood and did not impact sensorimotor gating. Collectively, these results indicate that chemogenetic induction of Gi signaling in CaMKIIα-positive forebrain excitatory neurons in postnatal and juvenile temporal windows does not appear to impinge on the programming of anxiodepressive behaviors in adulthood.
Significance Statement
The experience of early adversity can program persistent alterations in mood-states. It has been suggested that a perturbation of signaling pathways within forebrain neurocircuits, in particular a disruption of the balance between Gq and Gi signaling in forebrain excitatory neurons during critical developmental epochs may program the dysregulation of anxiodepressive behaviors. Prior evidence indicates that increased Gq signaling-mediated activation of forebrain excitatory neurons in postnatal life can enhance adult anxiodepressive behaviors. Here, we have addressed whether Gi signaling-mediated inhibition of forebrain excitatory neurons in the postnatal and juvenile windows of life can influence adult anxiodepressive behaviors. Our findings indicate that chronic chemogenetic inhibition of forebrain excitatory neurons via Gi-mediated signaling during critical developmental time windows does not impact mood-related behavior.
Footnotes
The authors declare no competing financial interests.
The study was supported by project RTI4003 from the Department of Atomic Energy to Tata Institute of Fundamental Research, and by the Sree Ramakrishna Paramahamsa Research Grant (2020) from the Sree Padmavathi Venkateswara Foundation (SreePVF), Vijayawada, Andhra Pradesh.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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