Memantine improves cognitive deficits via KATP channel inhibition in olfactory bulbectomized mice

• Published in: Molecular and cellular neuroscience 2021-12, Vol.117, p.103680-103680, Article 103680
• Main Authors: Moriguchi, Shigeki, Inagaki, Ryo, Fukunaga, Kohji
• Format: Article
• Language: English
• Subjects: CaMKII; CaMKIV; Cognitive deficits; KATP channel; Memantine; OBX mice
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2021.103680

Patients with Alzheimer's disease (AD) demonstrate severely impaired olfactory systems, which occur in the early stages of the disease. Olfactory bulbectomy (OBX) in mice elicits cognitive deficits, and reduces cholinergic activity in the hippocampus. Here, we confirmed that the novel AD drug memantine rescues cognitive deficits via ATP-sensitive potassium (KATP) channel inhibition in OBX mice. Repeated memantine administration at 1–3 mg/kg p.o. for 14 days starting at 10 days after OBX surgery significantly rescued cognitive deficits in OBX mice, as assessed using Y-maze, novel object recognition, and passive avoidance tasks. Consistent with the rescued cognitive deficits in OBX mice, long-term potentiation (LTP) in the hippocampal cornu ammonis (CA) 1 region was markedly restored with memantine administration. As demonstrated by immunoblotting, the reductions of calcium/calmodulin-dependent protein kinase II (CaMKII) α (Thr-286) autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV; Thr-196) phosphorylation in the CA1 region of OBX mice were significantly restored with memantine. Conversely, pre-treatment with pinacidil, a KATP channel opener, failed to reinstate hippocampal LTP and CaMKII/CaMKIV activities in the CA1 region. Finally, improvement of cognitive deficits by memantine treatments was observed in OBX-operated Kir6.1 heterozygous (+/−) mice but not in OBX-operated Kir6.2 heterozygous (+/−) mice. Overall, our study demonstrates that memantine rescues OBX-induced cognitive deficits via Kir6.2 channel inhibition in the CA1 region. •Memantine significantly improved cognitive deficits and hippocampal LTP in OBX mice.•Memantine significantly restored decreased CaMKII and CaMKIV activities in CA1 of OBX mice.•Memantine failed to improve cognitive deficits in OBX-operated Kir6.2+/- mice, but not in OBX-operated Kir6.1+/-mice.Repeated memantine administration at 3 mg/kg p.o. failed to improve cognitive deficits in OBX-operated Kir6.2+/- mice, but not in OBX-operated Kir6.1+/- mice.