Early adversity is a key risk factor for the development of several psychiatric disorders, including anxiety and depression. During early life, neurocircuits that regulate emotionality undergo substantial structural remodeling and functional maturation, and are thus particularly susceptible to modification by environmental experience. Preclinical evidence indicates that early stress enhances adult anxio-depressive behaviors. A commonality noted across diverse early stress models is life-long alterations in neuroendocrine stress responses and monoaminergic neurotransmission in key limbic circuits. Dysregulation of G protein-coupled receptor (GPCR) signaling is noted across multiple early stress models and is hypothesized to be an important player in the programming of aberrant emotionality. This raises the possibility that disruption of GPCR signaling in key limbic regions during critical temporal windows could establish a substrate for enhanced risk of adult psychopathology. Here, we review literature, predominantly from preclinical models, which supports the building hypothesis that a disruption of GPCR signaling could play a central role in programming persistent molecular, cellular, functional, and behavioral changes as a consequence of early adversity.

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.

Early adversity is a key risk factor for the development of adult psychopathology, including anxiety, depression and schizophrenia. Rodent models of early adversity program persistent behavioral, molecular, metabolic, and neurophysiological changes. Perturbed signaling via forebrain Gq-coupled neurotransmitter receptors is a common feature across multiple models of early adversity. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke long-lasting mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of CamKIIα-positive forebrain excitatory neurons during postnatal life (P2-14) increased anxietyand despair-like behavior, and evoked sensorimotor gating deficits in adulthood. In contrast, chronic chemogenetic hM3Dq DREADD activation of forebrain excitatory neurons in the juvenile or adult window did not evoke any mood-related behavioral alterations, highlighting the criticality of the postnatal temporal window. The enhanced anxiety-, despair-and schizophrenia-like behavioral changes evoked by chronic chemogenetic activation of forebrain excitatory neurons in postnatal life, was accompanied by an increased cortical and hippocampal metabolic rate of glutamatergic and GABAergic neurons in adulthood. Furthermore, animals with a history of postnatal hM3Dq activation exhibited a decline in the expression of activitydependent and plasticity-associated markers within the hippocampus, along with perturbed hippocampal excitatory and inhibitory currents in adulthood. 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 metabolic and neurophysiological changes in forebrain glutamate and GABA systems, recapitulating specific aspects of the consequences of early adversity.

G-protein-coupled receptors (GPCRs) coupled to G i 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 G i 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 G i 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 CaMKIIα-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 G i 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.

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