Thalamic reticular nucleus impairments and abnormal prefrontal control of dopamine system in a developmental model of schizophrenia: prevention by N-acetylcysteine

Abstract

Recent evidence showed thalamic abnormalities in schizophrenia involving disruptions to the parvalbumin neurons in the thalamic reticular nucleus (TRN). However, their functional consequences, as well as a potential linkage to oxidative stress, are unclear. The TRN is posited to gate prefrontal control of dopamine neuron activity in the ventral tegmental area (VTA). Thus, we hypothesized that schizophrenia-related TRN abnormalities might contribute to dopamine dysregulation, a well-known feature of the disorder. To test this, in adult rats exposed prenatally to methylazoxymethanol acetate (MAM rats), oxidative impairments to the parvalbumin neurons in the anterior TRN were assessed by immunohistochemistry. Using in vivo electrophysiology, we investigated whether inactivation of the prefrontal cortex would produce differential effects on VTA dopamine neurons in MAM rats. We show that MAM rats displayed reduced markers of parvalbumin and wisteria floribunda agglutinin-labeled perineuronal nets, correlating with increased markers of oxidative stress (8-oxo-7, 8-dihydro-20-deoxyguanosine and 3-Nitrotyrosine). Moreover, MAM rats displayed heightened baseline and abnormal prefrontal control of VTA dopamine neuron activity, as tetrodotoxin-induced inactivation of the infralimbic prefrontal cortex decreased the dopamine population activity, contrary to the normal increase in controls. Such dopamine neuron dysregulation was recapitulated by enzymatic perineuronal net digestion in the TRN of normal rats. Furthermore, juvenile (postnatal day 11-25) antioxidant treatment (N-acetyl-cysteine; 900mg/L; drinking water) prevented all these impairments in MAM Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

The Antioxidant N-Acetyl-L-Cysteine Restores the Behavioral Deficits in a Neurodevelopmental Model of Schizophrenia Through a Mechanism That Involves Nitric Oxide

“…Therefore, NAC could also prevent a delayed maturation of perineuronal net and PV positive interneurons. It is interesting to note that the treatment with NAC before weaning was able to revert the increased dopaminergic activity in the ventral tegmental area and recover the loss of PV interneurons and the perineuronal net in the thalamic reticular nucleus in MAM rats ( Zhu et al, 2021 ). Since the oxidative stress prevents the maturations of the perineuronal net and, consequently, the PV cells, NAC could act by preventing and recovering that delayed maturation.…”

“…Those rats also showed a reduction in the PV positive interneurons density in the ventral hippocampus and PFC ( Penschuck et al, 2006 ; Du and Grace, 2016 ; Perez et al, 2019b ), increased ventral tegmental area activity, oxidative stress, and neuroinflammatory markers ( Zhu et al, 2021 ). Interestingly, the treatment with NAC during the prepubertal stage of development prevented the increased activity of the ventral tegmental area in MAM rats ( Zhu et al, 2021 ).…”

Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

“…Preclinical studies (in MAM rat model or via selective manipulation of PV neurons) have highlighted that PV neuron impairment in ventral hippocampus/subiculum or thalamus reticular nucleus result in overactive ventral-subiculum leading to an increased number of active dopaminergic neurons in the ventral-tegmental-area, which in turn drive elevated dopamine neurotransmission in the mesolimbic system [67,[151][152][153] (Fig. 1).…”

“…Indeed, as evidenced by the pioneer works of Grace and collaborators, an increased ventral hippocampal activity causes the nucleus accumbens to strongly inhibit the ventral pallidum, which in turn increases the number of spontaneously active ventral-tegmental-area dopamine neurons [151,154]. Interestingly in MAM rats, OxS-induced impairments of PV neurons in thalamus reticular nucleus [56] lead to the disinhibition of the multisynaptic excitatory pathway "infralimbic-cortex/reuniens/ventral-subiculum", contributing to the ventral-subiculum hyperactivity and the consequent dopamine hyperactivity [153]. NAC treatment prevented the PV deficits in thalamus reticular nucleus and dopamine dysfunction, suggesting that early antioxidant treatment might contribute to dopamine normalization in schizophrenia.…”

Use of prepubertal environment enrichment to prevent dopamine dysregulation in a neurodevelopmental rat model of schizophrenia risk

“…Instead, our study emphasized a novel potential of EE, and tested whether prepubertal EE can prevent physiological alterations in the MAM model proposed to underlie psychosis, namely the aberrant ventral tegmental area (VTA) DA neuron and elevated vHipp pyramidal neuron firings ( Grace, 2016 ). Such preventative efficacy can be assessed by in vivo single unit recordings, of which the technical details can be found in our recent publications ( Gomes et al., 2019a ; Zhu et al., 2021 ).…”