GPCR signaling: role in mediating the effects of early adversity in psychiatric disorders

Abstract

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.

Chronic hM4Di-DREADD mediated chemogenetic inhibition of forebrain excitatory neurons in postnatal or juvenile life does not alter adult mood-related behavior

“…Converging evidence across diverse models of early stress has implicated perturbations in GPCR signaling during these critical periods in the establishment and eventual emergence of disrupted anxio-depressive behaviors (Benekareddy et al, 2011; Pati et al, 2020; Sarkar et al, 2014; Soiza-Reilly et al, 2018; Teissier et al, 2019; Vinkers et al, 2010a). This has led to a hypothesis that a balance between Gq and Gi-mediated GPCR signaling within neocortical brain regions during these early developmental windows may be important to shaping the development of trait anxiety and behavioral despair (Lambe et al, 2011; Tiwari et al, 2021). A recent study has shown that enhanced Gq-signaling via chemogenetic hM3Dq-DREADD mediated activation of CamKIIα-positive forebrain excitatory neurons during the postnatal, but not the juvenile or adult, temporal windows results in long-lasting increases in anxiety and despair-like behavior, accompanied by perturbed sensorimotor gating and pre-pulse inhibition (PPI) deficits (Pati et al, 2020).…”

“…It has been hypothesized that early stress may shift the balance towards enhanced excitatory Gq-coupled signaling accompanied by a decline in inhibitory Gi-coupled signaling in forebrain neurocircuits, which could contribute to the programing of perturbed anxiety and despair-like behaviors (Lambe et al, 2011; Sumner et al, 2008; Tiwari et al, 2021). Chemogenetic studies indicate that enhanced Gq-signaling in forebrain excitatory neurons during postnatal life programs long-lasting increases in anxiety and despair-like behavior along with disrupted sensorimotor gating (Pati et al, 2020).…”

“…While exposure to early stress and trauma is associated with persistent increases in anxiety and despair-like behavior in preclinical studies (Chen and Baram, 2016;De Melo et al, 2018;Targum and Nemeroff, 2019;Wang et al, 2020), enriched environment exposure (Cymerblit-Sabba et al, 2013;Francis et al, 2002;Kempermann et al, 1997;Ravenelle et al, 2014;Sparling et al, 2018) and high maternal care during these early temporal windows is associated with enhanced stress-coping and resilient behavioral responses (Bagot et al, 2009;Bredy et al, 2003;Champagne et al, 2008). The neurotransmitter, serotonin (5-HT), and signaling via the Gi-coupled 5-HT1A and Gq-coupled 5-HT2A receptors, has been implicated in playing an important role in shaping the development of mood-related behavior (Altieri et al, 2015;Gordon and Hen, 2004;Tiwari et al, 2021). Elevation of 5-HT levels during postnatal life, either via pharmacological blockade or genetic loss of function of the 5-HT transporter, is associated with enhanced anxiety and despair-like behavior that persists across the life-span (Ansorge et al, 2004(Ansorge et al, , 2008Sarkar et al, 2014).…”

“…It has been hypothesized that early stress may shift the balance towards enhanced excitatory Gq-coupled signaling accompanied by a decline in inhibitory Gi-coupled signaling in forebrain neurocircuits, which could contribute to the programing of perturbed anxiety and despair-like behaviors (Lambe et al, 2011;Sumner et al, 2008;Tiwari et al, 2021).…”

Transcriptome Profiling of Dysregulated GPCRs Reveals Overlapping Patterns across Psychiatric Disorders and Age-Disease Interactions

“…Indeed almost all neurotransmitters involved in psychiatric disorders act directly through GPCRs [ 19 , 20 ]. Examples include but are not limited to serotonin and noradrenaline (depression and bipolar disorder) and dopamine (schizophrenia) (for review, see [ 21 , 22 , 23 , 24 , 25 ]). Lastly, GPCRs are the most common targets for drugs currently used to treat psychiatric disorders, and most neuropharmacological drugs are known to regulate GPCR activity in the CNS [ 21 , 22 ].…”