Reduction of glutamatergic activity through cholinergic dysfunction in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice

Abstract Cholinergic activation can enhance glutamatergic activity in the hippocampus under pathologic conditions, such as Alzheimer’s disease and Lewy body disease. We aimed to elucidate the relationship between glutamatergic neural suppression and cholinergic neural dysfunction. We reported the importance of hippocampal cholinergic neurostimulating peptide (HCNP) in inducing acetylcholine synthesis in the MSN. Here, we demonstrated that HCNP-precursor protein (pp) knockout (KO) mice electrophysiologically presented with glutamatergic dysfunction in the hippocampus with age. The impairment of cholinergic dysfunction and the vesicular acetylcholine transporter decrease in the pre-synapse with reactive upregulation of the muscarinic M1 receptor may be partly involved in glutamatergic dysfunction in the hippocampus of HCNP-pp KO mice. These results in combination with our previous reports support the reduction of hippocampal theta power as region-specific in the stratum oriens of CA1 and a decrease in choline acetyltransferase and a direct reduction in acetylcholine in the hippocampus. This may support that HCNP-pp KO mice are an adequate genetic model for cholinergic functional impairment in septo-hippocampal interactions. Thus, according to cholinergic hypothesis this model mice might have a potential as a partial pathological animal model for Alzheimer’s disease.