Atypical antipsychotics improve positive and negative symptoms but are not effective for treating cognitive impairments in patients with schizophrenia. We previously reported that cognitive impairments in neonatal ventral hippocampus (NVH)-lesioned rats show resistance to atypical antipsychotics risperidone and are associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) signaling in memory-related regions. The cognitive enhancer ST101 (spiro[imi-dazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) stimulates CaMKII activity in the hippocampus and medial prefrontal cortex (mPFC). We thus tested ST101 on cognitive impairments in NVH-lesioned rats. Chronic ST101 administration (0.1 and/or 0.5 mg/kg, p.o.) significantly improved deficits in prepulse inhibition (PPI), social interaction, and cognitive function in NVH-lesioned rats. ST101 administration (0.5 mg/kg, p.o.) significantly restored the decreased CaMKII autophosphorylation (Thr-286) in the mPFC and hippocampal CA1 regions of NVH-lesioned rats when assessed by immunohistochemistry. Chronic ST101 administration (0.1 mg/kg, p.o.) improved the decline in phosphorylation levels of CaMKII (Thr-286), PKCα (Ser-657), α-amino-3-hydroxy-5-methyl-4-isoxazol- propionic acid (AMPA)-type glutamate receptor subunit 1 (GluA1: Ser-831), and N-methyl-d-aspartate (NMDA) receptor subunit 1 (GluN1: Ser-896) in the mPFC and hippocampal CA1 regions. Taken together, these results suggest that ST101 improves schizophrenia-like behaviors and cognitive impairment by enhancing CaMKII/PKCα signaling in the mPFC and hippocampus in NVH-lesioned rats.
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