RESUMO
The environmental disturbances in a critical neurodevelopmental period exert organizational effects on brain intrinsic plasticity including excitatory and inhibitory (E/I) neurotransmission those can cause the onset of psychiatric illness. We previously reported that treatment of neural precursor cells with N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 induced reduction of GABAergic interneuron differentiation, and these changes recovered by atypical antipsychotic blonanserin treatment in vitro. However, it remains unclear how this treatment affects neural circuit changes in hippocampus and amygdala, which might contribute to the prevention of onset process of schizophrenia. To elucidate the pathogenic/preventive mechanisms underlying prenatal environmental adversity-induced schizophrenia in more detail, we administered poly (I:C) followed by antipsychotics and examined alterations in social/cognitive behaviors, GABA/glutamate-related gene expressions with cell density and E/I ratio, and brain-derived neurotrophic factor (Bdnf) transcript levels, particularly in limbic areas. Treatment with antipsychotic blonanserin ameliorated impaired social/cognitive behaviors and increased parvalbumin (PV)-positive (+) cell density and its mRNA levels as well as Bdnf with long 3'UTR mRNA levels, particularly in the dorsal hippocampus, in rats exposed to maternal immune activation (MIA). Low dose of blonanserin and haloperidol altered GABA and glutamate-related mRNA levels, the E/I ratio, and Bdnf long 3'UTR mRNA levels in the ventral hippocampus and amygdala, but did not attenuate behavioral impairments. These results strongly implicate changes in PV expression, PV(+) GABAergic interneuron density, and Bdnf long 3'UTR expression levels, particularly in the dorsal hippocampus, in the pathophysiology and treatment responses of MIA-induced schizophrenia and highlight the therapeutic potential of blonanserin for developmental stress-related schizophrenia.
Assuntos
Antipsicóticos , Células-Tronco Neurais , Feminino , Gravidez , Ratos , Animais , Antipsicóticos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Regiões 3' não Traduzidas , Células-Tronco Neurais/metabolismo , Interneurônios , Hipocampo/metabolismo , Tonsila do Cerebelo/metabolismo , Ácido gama-Aminobutírico/metabolismo , Glutamatos/farmacologiaRESUMO
BACKGROUND: There has been number of studies suggesting experiences of adversity in early life interrelated subsequent brain development, however, neurobiological mechanisms confer risk for onset of psychiatric illness remains unclear. METHODS: In order to elucidate the pathogenic mechanisms underlying early life adversity-induced refractory depression in more detail, we administered corticosterone (CORT) to adolescent rats with or without prenatal ethanol exposure followed by an antidepressant or antipsychotic and examined alterations in depressive and social function behaviors and brain-derived neurotrophic factor (BDNF) levels in serum, the hippocampus, anterior cingulate cortex, and nucleus accumbens. RESULTS: The combined stress exposure of prenatal ethanol and adolescent CORT prolonged immobility times in the forced swim test (FST), and increased investigation times and numbers in the social interaction test (SIT). A treatment with escitalopram reversed depression-like behavior accompanied by reductions in BDNF levels in serum and the nucleus accumbens, while a treatment with blonanserin ameliorated abnormal social interaction behavior with reductions in serum BDNF levels. LIMITATIONS: Further studies are needed to clarify the clinical evinces responding to these results, and many questions remain regarding the mechanisms by which refractory depression and antidepressant/antipsychotic treatments cause changes in serum and brain regional BDNF levels. CONCLUSION: These results strongly implicate changes in BDNF levels in serum and the nucleus accumbens in the pathophysiology and treatment of early life combined stress-induced depression and highlight the therapeutic potential of escitalopram and new generation antipsychotic blonanserin for treatment-resistant refractory depression.