Neonatal inflammation via persistent TGF-I31 downregulation decreases GABAAR expression in basolateral amygdala leading to the imbalance of the local excitation-inhibition circuits and anxiety-like phenotype in adult mice

Neonatal inflammation can increase the risk of anxiety disorder in adulthood. The balance between glutamatergic excitatory and GABAergic inhibitory transmissions in the basolateral amygdala (BLA) plays a vital role in controlling anxiety state. Based on the reports that early-life inflammation had adverse effects on GABAergic system, the aim of this study was to investigate whether and how neonatal inflammation affects excitatoryinhibitory circuits in the BLA resulting in anxiety disorder. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 mu g/kg) or saline on postnatal days 3-5. LPS-treated mice developed anxiety behaviors accompanied by the hyperactivity of adrenal axis in adulthood. Electrophysiological study revealed the increase of postsynaptic neuronal excitability in the cortical-BLA excitatory synapses of LPS mice which could be recovered by bath-application of GABAAR agonist suggesting the impairment of GABAergic system in LPS mice. Compared with controls, GABAAR alpha 2 subunit expression and density of GABA-evoked current in BLA principal neurons were reduced in LPS mice. Additionally, neonatal LPS treatment resulted in the downregulation of transforming growth factor-beta 1 (TGF-I31) expression and PKC signaling pathway in the adult BLA. The local TGF-I31 overexpression in the BLA improved GABAAR alpha 2 expression via up-regulating the activity of PKC signaling, which corrected GABAAR-mediated inhibition leading to the abolishment of anxiety-like change in adrenal axis regulation and behaviors in LPS mice. These data suggest the persistent TGF-I31deficit induces the down-regulation of GABAAR alpha 2 expression and subsequent disruption of the excitation-inhibition balance in the BLA circuits, which is the important mechanisms of neonatal inflammation-induced anxiety disorder.

Automated summary

Neonatal inflammation can increase the risk of anxiety disorder in adulthood. The balance between glutamatergic excitatory and GABAergic inhibitory transmissions in the basolateral amygdala (BLA) plays a vital role in controlling anxiety state. This study found that neonatal inflammation affects excitatory-inhibitory circuits in the BLA, resulting in anxiety disorder. The impairment of the GABAergic system and downregulation of TGF-β1 expression were identified as important mechanisms.