Developmental oxidative stress leads to T-type Ca2+ channel hypofunction in thalamic reticular nucleus of mouse models pertinent to schizophrenia

Abstract

Impairment of parvalbumin interneurons induced by oxidative stress (OxS) is a "hub" on which converge several genetic and environmental risk factors associated with schizophrenia. In patients, this could be a mechanism leading to anomalies of the thalamic reticular nucleus (TRN) whose major neuronal population expresses parvalbumin. The TRN shapes the information flow within thalamo-cortical circuits. The low-threshold voltage-gated T-type Ca²⁺ (T-Ca²⁺) channels (CaV3.2, CaV3.3) contribute to the excitability and rhythmic bursting of TRN neurons which mediates cortical sleep spindles, known to be affected in schizophrenia. Here, we investigated the impact of OxS during postnatal development and adulthood on firing properties and T-Ca²⁺ channels of TRN neurons. In Gclm knock-out (KO) mice, which display GSH deficit and OxS in TRN, we found a reduction of T-Ca²⁺ current density in adulthood, but not at peripuberty. In KO adults, the decreased T-Ca²⁺ currents were accompanied with a decrease of CaV3.3 expression, and a shift towards more hyperpolarized membrane potentials for burst firing leading to less prominent bursting profile. In young KO mice, an early-life oxidative challenge precipitated the hypofunction of T-Ca²⁺ channels. This was prevented by a treatment with N-acetylcysteine. The concomitant presence of OxS and hypofunction of T-Ca²⁺ channels were also observed in TRN of a neurodevelopmental model relevant to psychosis (MAM mice). Collectively, these data indicate that OxS-mediated T-Ca²⁺ hypofunction in TRN begins early in life. This also points to T-Ca²⁺ channels as one target of antioxidant-based treatments aiming to mitigate abnormal thalamo-cortical communication and pathogenesis of schizophrenia.