The disruption of neurodevelopment is a hypothesis for the emergence of schizophrenia. Some evidence supports the hypothesis that a redox imbalance could account for the developmental impairments associated with schizophrenia. Additionally, there is a deficit in glutathione (GSH), a main antioxidant, in this disorder. The injection of metilazoximetanol acetate (MAM) on the 17th day of gestation in Wistar rats recapitulates the neurodevelopmental and oxidative stress hypothesis of schizophrenia. The offspring of rats exposed to MAM treatment present in early adulthood behavioral and neurochemical deficits consistent with those seen in schizophrenia. The present study investigated if the acute and chronic (250 mg/kg) treatment during adulthood with N-acetyl-L-cysteine (NAC), a GSH precursor, can revert the behavioral deficits [hyperlocomotion, prepulse inhibition (PPI), and social interaction (SI)] in MAM rats and if the NAC-chronic-effects could be canceled by L-arginine (250 mg/kg, i.p, for 5 days), nitric oxide precursor. Analyses of markers involved in the inflammatory response, such as astrocytes (glial fibrillary acid protein, GFAP) and microglia (binding adapter molecule 1, Iba1), and parvalbumin (PV) positive GABAergic, were conducted in the prefrontal cortex [PFC, medial orbital cortex (MO) and prelimbic cortex (PrL)] and dorsal and ventral hippocampus [CA1, CA2, CA3, and dentate gyrus (DG)] in rats under chronic treatment with NAC. MAM rats showed decreased time of SI and increased locomotion, and both acute and chronic NAC treatments were able to recover these behavioral deficits. L-arginine blocked NAC behavioral effects. MAM rats presented increases in GFAP density at PFC and Iba1 at PFC and CA1. NAC increased the density of Iba1 cells at PFC and of PV cells at MO and CA1 of the ventral hippocampus. The results indicate that NAC recovered the behavioral deficits observed in MAM rats through a mechanism involving nitric oxide. Our data suggest an ongoing inflammatory process in MAM rats and support a potential antipsychotic effect of NAC.
Astrocytes are active cells that respond to neurotransmitters with elevations in their intracellular calcium concentration (calcium signals). In a tripartite synapse involving two neurons coupled by a glutamatergic synapse and one astrocyte, glutamate released by the presynaptic neuron can generate calcium signals in the astrocyte, which in turn trigger the release of neuroactive molecules (gliotransmitters) by the astrocyte that bind to receptors in the pre- and postsynaptic neuron membranes and modulate synaptic transmission. Astrocytic calcium signals can also be evoked by dopamine released in distant sites. Little is known about how dopamine modulates glutamatergic-evoked astrocyte activity. To investigate this question, we constructed compartmental astrocyte models with three different morphologies: linear (soma plus a single branch); branched (soma plus two branches); and bifurcated (soma plus a single branch that bifurcates into two branchlets). Compartments were modeled by conductance-based equations for membrane voltage and transport of ions, glutamate and dopamine between extra- and intracellular spaces. Glutamatergic and dopaminergic stimuli were modeled as Poisson processes with variable frequencies, and astrocyte responses were measured by number and location of evoked calcium signals. For cells with linear morphology, whole-cell dopaminergic stimulation reduced the glutamatergic stimulation frequency of distal compartments needed to generate calcium signals. For both the branched and bifurcated morphologies, whole-cell dopaminergic stimulation together with glutamatergic stimulation of one of the processes reduced the glutamatergic stimulation frequency necessary to trigger a calcium signal in the other process. The same glutamatergic stimulation protocols without dopamine stimulation required higher glutamatergic input frequencies to evoke calcium signals. Our results suggest that dopamine facilitates the occurrence of glutamatergic-evoked calcium signals, and that dopamine-glutamate interaction can control the distribution of calcium signals along the astrocyte extension.
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