Adjunctive clozapine with bright light mitigates cognitive deficits by synaptic plasticity and neurogenesis in sub-chronic MK-801 treated mice

Schizophrenia impacts about 1 % of the global population, with clozapine (CLZ) being a critical treatment for refractory cases despite its limitations in effectiveness and adverse effects. Therefore, the search for more effective treatments remains urgent. Light treatment (LT) recognized for enhancing cognition and mood, presents a promising complementary approach. This study investigated the effects of CLZ and LT on cognitive impairments in a sub-chronic MK-801 induced schizophrenia mouse model. Results showed that both CLZ and CLZ + LT treatment elevate cognitive performance of sub-chronic MK-801 treated mice in serial behavioral tests over two months. Histological analysis revealed increased dendritic spine density and branching, and synaptic repair in the hippocampus with CLZ and CLZ + LT interventions. Furthermore, both treatments increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus, likely contributing to cognitive amelioration in MK-801 treated mice. Additionally, BrdU labeling revealed that CLZ + LT further enhances neurogenesis in the dentate gyrus (DG) and lateral ventricle (LV) of sub-chronic MK-801 treated mice. These findings may have implications for the development of noninvasive and adjunctive treatment strategies aimed at alleviating cognitive impairments and improving functional outcomes in individuals with schizophrenia.