Cognitive impairment following maternal separation in the rat is regulated by effects of the NAD + /SIRT3 axis on hippocampal synaptic plasticity

Abstract

Abstract Maternal separation during early life can induce behaviors in adult animals that resemble those seen in schizophrenia, manifesting cognitive deficits. This may be indicative of oxidative stress linked to mitochondrial dysfunction. However, there is limited understanding of the molecular mechanisms regulating mitochondria in neural circuits that govern cognitive impairment relevant to schizophrenia, and their impact on neuronal structure and function. A 24-hour maternal separation (MS) rat model was utilized to simulate features associated with schizophrenia. Schizophrenia-associated behaviors and cognitive impairment were assessed using the open field test, pre-pulse inhibition, novel object recognition test, and Barnes maze test. The levels of mitochondrial proteins were measured using Western blot analysis. Additionally, alterations in mitochondrial morphology, reduced hippocampal neuronal spine density, and impaired LTP in the CA1 region were observed. Nicotinamide (NAM) supplementation, administration of honokiol (HNK) (a SIRT3 activator), or overexpression of SIRT3 could inhibit this process. Conversely, administration of 3-TYP (a SIRT3 inhibitor) in control and NAM-treated MS rats led to deficits in behavior, mitochondrial morphology, and the hippocampal neuronal phenotype. Our findings suggested a causal role for the NAD+/SIRT3 axis in modulating cognitive behaviors via effects on hippocampal neuronal synaptic plasticity. The NAD+/SIRT3 axis could be considered a promising therapeutic target for addressing cognitive-related behavioral disturbances, such as those seen in schizophrenia.