Deep patch-clamp recordings in awake mice from medial septal neurons during hippocampal sharp-wave ripples

OBJECTIVES: The medial septum modulates hippocampal oscillations, including ripples, which are critical for memory consolidation. While the role of the medial septum in theta rhythms is well-established, its specific contribution to hippocampal ripple activity remains poorly understood. This study sought to investigate the relationship between medial septal activity and hippocampal ripples in vivo . METHODS: This study aimed to characterize the in-vivo membrane potential dynamics of putative medial septal neuron subtypes and their contribution to hippocampal ripples in awake mice. We performed in-vivo whole-cell patch-clamp recordings from medial septal neurons in head-fixed, awake mice, while simultaneously acquiring hippocampal local field potentials. RESULTS: Medial septal neurons were classified into glutamatergic, cholinergic, and GABAergic subtypes using hierarchical clustering based on their intrinsic electrophysiological properties. We analyzed the firing rates and subthreshold membrane potential dynamics of these neurons during hippocampal ripple events and examined their correlations with ripple parameters (duration, frequency, and power). Our results revealed subtype-specific responses. Notably, putative glutamatergic neurons exhibited a slight decrease in firing rate, yet displayed a pronounced depolarization of their membrane potential approximately 100 ms before ripple onset, peaking at the initiation of ripples. This depolarization was inversely correlated with subsequent ripple amplitude and power. In addition, membrane hyperpolarization was positively correlated with ripple duration. CONCLUSION: These findings elucidate the contribution of glutamatergic medial septal neurons to hippocampal ripple dynamics and suggest a tightly regulated interaction between the medial septum and hippocampus in shaping ripple activity.