Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling

Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD. •Maternal deprivation (MD) did not affect AMPAR-mediated synaptic transmission in VTA DA neurons•MD induced both pre- and postsynaptic GABAergic LTD•MD induced GABAergic metaplasticity through disruption of AKAP150 signaling•GABAergic synaptic and AKAP signaling deficits were rescued by HDAC inhibition Childhood adversities increase the risk of later psychopathology via dopamine dysregulation. Authement et al. demonstrate that early maternal deprivation induced GABAergic metaplasticity in ventral tegmental area dopamine neurons through reversible epigenetic mechanisms that involve the scaffolding A-kinase anchoring protein (AKAP79/150).