Anti-Aging Protein Klotho Attenuates Schizophrenia-Associated Cognitive and Synaptic Dysfunctions by Regulating GluN2B-NMDARs in the Hippocampus

Cognitive impairment is a core symptom of schizophrenia and has a significant impact on clinical efficacy and prognosis. However, its underlying pathological mechanism remains unclear and effective treatments are still lacking. N-methyl-D-aspartate receptors (NMDARs) hypofunction is the key pathological basis of cognitive impairments in schizophrenia and the anti-aging protein klotho is involved in the regulation of NMDAR function. Our current study aims to investigate the role of klotho in synaptic and cognitive function in a male rat model of schizophrenia, in which rats are briefly exposed to dizocilpine (MK-801) to disrupt NMDAR during early development. We found that MK-801 treatment resulted in hippocampus-dependent synaptic plasticity and cognitive deficits in male rats during adulthood, and the expression of klotho protein in the hippocampus was significantly decreased in these rats. Elevation of hippocampal klotho in MK-801-treated rats via gene overexpression can significantly reverse the synaptic and cognitive dysfunction. At the molecular level, elevation of hippocampal klotho selectively upregulated the total and synaptic expressions of GluN2B-containing NMDARs, significantly increased postsynaptic density protein 95 (PSD-95) level and promoted extracellular signal-regulated kinase (ERK) phosphorylation in the hippocampus of MK-801-treated rats. Furthermore, treatment with a specific GluN2B antagonist Ro 25-6981 significantly abolished the beneficial effects of klotho on hippocampal long-term potentiation (LTP) and cognition in MK-801-treated rats. Collectively, reduced klotho in the hippocampus may contribute to the development of MK-801-induced schizophrenia-like synaptic and cognitive deficits, and elevating klotho is capable of rescuing the synaptic plasticity and cognition by modulating hippocampal GluN2B-containing NMDARs.