BackgroundChronic stress is generally known to exacerbate the development of numerous neuropsychiatric diseases such as fear and anxiety disorders, which is at least partially due to the disinhibition of amygdala subsequent to the prolonged stress exposure. GABA receptor A (GABAAR) mediates the primary component of inhibition in brain and its activation produces two forms of inhibition: the phasic and tonic inhibition. While both of them are critically engaged in limiting the activity of amygdala, their roles in the amygdala disinhibition subsequent to chronic stress exposure are largely unknown.ResultsWe investigated the possible alterations of phasic and tonic GABAAR currents and their roles in the amygdala disinhibition subsequent to chronic stress. We found that both chronic immobilization and unpredictable stress led to long lasting loss of tonic GABAAR currents in the projection neurons of lateral amygdala. By contrast, the phasic GABAAR currents, as measured by the spontaneous inhibitory postsynaptic currents, were virtually unaltered. The loss of tonic inhibition varied with the duration of daily stress and the total days of stress exposure. It was prevented by pretreatment with metyrapone to block corticosterone synthesis or RU 38486, a glucocorticoid receptor antagonist, suggesting the critical involvement of glucocorticoid receptor activation. Moreover, chronic treatment with corticosterone mimicked the effect of chronic stress and reduced the tonic inhibition in lateral amygdala of control mice. The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment.ConclusionsOur study suggests that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress. We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases.

Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function. The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence. We investigate the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS. To test this, multiple cohorts of Sprague Dawley rats were injected with LPS on P14. In adolescence, rats were subjected to behavioral testing in a reciprocal social interaction paradigm as well as the open field. We quantified eCB levels in the amygdala of P14 and adolescent animals (anandamide and 2-arachidonoylglycerol) as well as adolescent amygdaloid cannabinoid receptor 1 (CB1) binding site density and the hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which metabolizes the eCB anandamide. Additionally, we examined the impact of FAAH inhibition on alterations in social behavior. Our results indicate that P14 LPS decreases adolescent social behavior (play and social non-play) in males and females at P40. This behavioral alteration is accompanied by decreased CB1 binding, increased anandamide levels and increased FAAH activity. Systemic administration of the FAAH inhibitor PF-04457845 (1mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.

Bisphenol A (BPA), one of the most common environmental endocrine disruptors, has been recognized to have wide adverse effects on the brain development and behavior. These adversities are related to its ability to bind estrogen receptor (ER) with subsequent alteration of its expression in the target areas. However, very little is known about whether BPA exposure also affects ER phosphorylation and its translocation to nucleus during postnatal development, two critical steps for its function. Here, we found that during development from postnatal day 7 (P7) to P21, the alpha subtype of ER (ERα) in the hippocampus of male rats experienced remarkable alterations in terms of its expression, phosphorylation and translocation to nucleus. Exposure to low level of BPA had bidirectional, development-dependent effects on the expression of ERα mRNA and protein, but decreased ERα phosphorylation and impaired its translocation to nucleus throughout the period investigated. Treatment with low dose of ICI 182,780 (ICI), an ER antagonist to block the binding of ER with BPA, reversed the altered ERα following BPA exposure, highlighting critical involvement of ER. Moreover, ICI treatment rescued the hippocampus-dependent behavioral deficits in the adult rats experiencing early-life BPA exposure. Overall, our results indicate that BPA interferes with the ERα signaling in the developing hippocampus in an ER-dependent manner, which may underlie its adverse behavioral and cognitive outcomes in adult animals.

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During early development, continuous exposure to environmental contaminants such as bisphenol A (BPA) is known to alter neuronal development, resulting in aberrant brain structure and predisposing individuals to developing neuropsychiatric disorders later in life. While the altered oligodendrocyte (OL) structure and function have been casually linked to the occurrence of numerous psychiatric diseases, it remains open whether early BPA exposure (EBE) also recruits OLs to mediate its toxicity in the brain. Here, we observed that EBE from birth to postnatal day 21 caused a substantial loss of hippocampal OLs in rat pups. The OL loss was enduring and manifested even when the affected pups spanned into their adulthood. In parallel, the expression of two key proteins in mature OLs, myelin basic protein (MBP), and monocarboxylate transporter 1 (MCT1) was markedly downregulated in adult hippocampus with a considerable reduction in the number of myelinated axons. By contrast, the myelination of individual axons remained intact. The altered hippocampal OLs were related to EBE-mediated disruption of estrogen receptor (ER) signaling in developing OLs and could be readily prevented by treatment with low level of ICI 182780, an ER antagonist. Importantly, the adult rats subject to EBE exhibited clear deficit in contextual fear memory, which highly correlated with OL loss and decreased MBP and MCT1 expression in hippocampus. The OL loss may thus represent an alternative route through which EBE has its adversity on the brain and contributes to the development of neuropsychiatric illness.