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.
Highlights
The thalamic reticular nucleus (TRN) is composed of GABAergic neurons that receive synaptic inputs from cortex, thalamus, and subcortical regions and exert inhibition onto thalamic neurons projecting to the cortex or subcortical areas [1,2,3,4,5]
We found a lower proportion of neurons displaying These suggest that oxidative stress (OxS)-mediated T-Ca2+ channel hypofunction bursting behavior at resting membrane potential (RMP) in KO
OxS reduced T-Ca2+ and small-conductance Ca2+-activated K+ (SK) current densities in TRN neurons of methylazoxymethanol acetate (MAM) mice We examined whether T-Ca2+ channels in TRN neurons were affected in another rodent model relevant to SZ, MAM mice
Summary
The thalamic reticular nucleus (TRN) is composed of GABAergic neurons that receive synaptic inputs from cortex, thalamus, and subcortical regions and exert inhibition onto thalamic neurons projecting to the cortex or subcortical areas [1,2,3,4,5]. We found a lower proportion of neurons displaying These suggest that OxS-mediated T-Ca2+ channel hypofunction bursting behavior at resting membrane potential (RMP) in KO during early-life represents a common, convergent mechanism (25.0%, 3/12) compared to WT mice (71.4%, 10/13, Fisher exact contributing to thalamo-cortical anomalies, sleep disturbances test, p = 0.02) (Fig. 1A), while neurons from both genotypes [28], and possibly risk for psychosis. Electrophysiology experiments We prepared brain slices from peripubertal (PND20-30) and young adult (PND60-75) mice and performed patch-clamp whole-cell recordings of TRN neurons in both current clamp (CC) and voltage clamp (VC) modes as described in Supplemental information. The decreased CaV3.3 expression was most prominent in anterior and medial TRN sub-regions (Fig. 1O) These results suggest that reduced CaV3.3 expression contributes to the reduced T-Ca2+ current density in TRN neurons of adult Gclm-KO mice
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