Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats

Abstract

Traumatic early life stress (ELS) is linked to dopamine (DA) dysregulation which increases the probability of developing psychiatric disorders in adolescence and adulthood. Our prior studies demonstrated that a severe early life stressor, a 24-hr maternal deprivation (MD) in juvenile male rats, could lead to altered DA signaling from the ventral tegmental area (VTA) due to impairment of GABAergic synaptic plasticity (promoting GABAergic long-term depression, LTD) with concomitant changes in the abundance of synaptic regulators including A-kinase anchoring protein (AKAP150).Importantly, these MD-induced synaptic changes in the VTA were accompanied by upregulation of histone deacetylase 2, histone hypoacetylation, and were reversible by HDAC inhibition. Using cell-attached and whole-cell patch clamp recordings, we found that MD stress also increased spontaneous VTA DA neuronal activity and excitability in juvenile male rats without affecting intrinsic excitability. Postsynaptic chemical disruption of AKAP150 and protein kinase A interaction increased VTA DA neuronal excitability in control non-MD rats mimicking the effects of MD on DA cell excitability with similar changes in membrane properties. Interestingly, this disruption decreased MD-induced VTA DA hyperexcitability. This MD-induced DA neuronal hyperexcitability could also be normalized at 24 hr after injection of the class 1 HDAC inhibitor, CI-994. Altogether, our data suggest that AKAP150 plays a critical role in the regulation of VTA DA neuronal excitability and that HDAC-mediated targeting of AKAP150 signaling could normalize VTA DA dysfunction following ELS thereby providing novel therapeutic targets for prevention of later life psychopathology. K E Y W O R D SAKAP, dopamine, epigenetics, HDAC, histone acetylation, VTA The authors declare no competing financial interests.

Effects of Early-Life Stress on the Brain and Behaviors: Implications of Early Maternal Separation in Rodents

“…Furthermore, methylation patterns across Drd1a CpG islands significantly increased compared to age-matched control mice ( Figure 2 ) [ 79 ]. Other recent studies have reported that histone deacetylase (HDAC) inhibition reduces VTA dopamine neuronal hyperexcitability involving AKAP150 signaling following MS in juvenile male rats [ 95 , 96 ]. In this paper, the authors indicated the potential use of HDAC inhibitors as a novel class of drugs for the prevention of MS-induced dopaminergic system dysfunction [ 97 ].…”

Early Life Stress- and Drug-Induced Histone Modifications Within the Ventral Tegmental Area

“…Additionally, MD also increased VTA DA neuronal excitability involving altered AKAP150 signaling (Shepard et al, 2020). Interestingly, administration of CI-994 (a selective class I histone deacetylase inhibitor, HDACi) recovered GABAergic plasticity, histone acetylation, BDNF abundance, (Authement et al, 2015;Shepard et al, 2018), and VTA DA excitability (Shepard et al, 2020). Indeed, transcriptional regulation of the Bdnf gene through histone modifications including deacetylation of H3K9 via HDAC2 has also been reported (Chen et al, 2003;Wang et al, 2014;Chen and Chen, 2017).…”

“…Specifically, HDAC2 was upregulated in VTA DA neurons with concomitant decreases in acetylation at H3K9 in protein isolates harvested from VTA tissues. Additionally, MD also increased VTA DA neuronal excitability involving altered AKAP150 signaling (Shepard et al, 2020). Interestingly, administration of CI-994 (a selective class I histone deacetylase inhibitor, HDACi) recovered GABAergic plasticity, histone acetylation, BDNF abundance, (Authement et al, 2015;Shepard et al, 2018), and VTA DA excitability (Shepard et al, 2020).…”

Resilience to anhedonia-passive coping induced by early life experience is linked to a long-lasting reduction of Ih current in VTA dopaminergic neurons

“…Similar to humans, in rodents the development of DAergic mesolimbic pathways seems to be largely sensitive to early life experiences ( Meaney et al, 2002 ; Brake et al, 2004 ; Peña et al, 2017 , 2019 ). The first 2 weeks of life seem to be particularly critical in rodents to shape the DAergic circuitry of the adult brain ( Gillies et al, 2014 ) and stress factors occurring early in life can induce transcriptional, structural and functional modifications in the VTA ( Chocyk et al, 2011 ; Authement et al, 2015 ; Penã et al, 2019 ; Masrouri et al, 2020 ; Shepard et al, 2020 ; Spyrka et al, 2020 ). In a nutshell, early experiences may impact the VTA and its DAergic network, thus influencing stress coping strategies and susceptibility or resilience to depression in adulthood.…”