HBK-15, a multimodal compound, induces procognitive effects through modulating hippocampal LTP and enhancing theta-gamma coupling in mice

Abstract

Abstract Neuropsychiatric disorders present with an array of emotional and behavioral symptoms, as well as cognitive deficits. Likely rooted in a complex pathophysiology involving glutamatergic neurotransmission imbalance, cognitive deficits frequently elude treatment by current pharmacotherapies. This highlights the pressing need for innovative drugs specifically targeting and ameliorating cognitive deficits in neuropsychiatric disorders. Here we show that HBK-15, a multimodal compound, exhibits robust antiamnesic properties across several MK-801-induced mouse models of memory deficits, likely through counteracting LTP decline and enhancing theta-gamma coupling in the hippocampus. HBK-15 has shown efficacy in mitigating MK-801-induced cognitive deficits across recognition, emotional, and spatial memory domains without impacting motor skill learning. Its protective effects spanned the encoding, consolidation, and retrieval phases of memory processing. Furthermore, the test compound counteracted the decrease in the hippocampal LTP magnitude caused by MK-801, probably via influencing the L-type voltage-gated calcium channels (Cav1.2). Interestingly, HBK-15 and MK-801 exhibited opposing effects on the coupling between theta and gamma oscillations in the hippocampus. The promotion of theta-gamma coupling by HBK-15 suggests that the compound holds promise for enhancing learning and memory processes. Overall, our research underscores the potential of HBK-15 and compounds of a similar receptor profile in developing effective therapeutic strategies for cognitive deficits in neuropsychiatric conditions such as depression or schizophrenia.