Robust Intrinsic Dorsoventral Organization of Hippocampal Sharp Wave–Ripples Persists During Cannabinoid Modulation

Background/Objectives: The hippocampus exhibits marked functional heterogeneity along its dorsoventral axis, with dorsal regions primarily supporting cognitive and spatial processing and ventral regions linked to emotional and stress-related functions. This functional gradient is shaped by intrinsic circuit properties and neuromodulatory systems, including the endocannabinoid system, whose cannabinoid type 1 (CB₁) receptors are abundantly expressed in the hippocampus. Sharp wave–ripple (SWR) complexes are highly organized network events that depend on precise excitation/inhibition balance and are essential for hippocampal information processing. The present study aimed to determine whether cannabinoid receptor activation or modulation influences SWRs and associated neuronal activity along the dorsoventral axis of the hippocampus. Methods: Extracellular field potentials and multiunit activity were recorded from the stratum pyramidale of the CA1 region in acute hippocampal slices obtained from dorsal and ventral segments. Spontaneous SWRs were analyzed under control conditions and following application of the CB₁ receptor agonists ACEA and WIN55,212-2, the cannabinoid compound cannabidiol (CBD), and the GIRK channel blocker tertiapin-Q. SWR incidence, waveform characteristics, and multiunit activity were quantified and compared between hippocampal segments. CB1 receptor expression was assessed in dorsal and ventral CA3 using Western blot analysis. Results: Baseline recordings revealed pronounced dorsoventral differences in SWR dynamics, with ventral hippocampus exhibiting higher SWR rates, larger amplitudes, and enhanced neuronal recruitment compared to dorsal hippocampus. In contrast, activation of CB₁ receptors by ACEA and WIN55,212-2, as well as application of CBD, did not significantly alter SWR occurrence, waveform properties, or associated multiunit activity in either hippocampal segment. Similarly, blockade of GIRK channels produced only limited effects, restricted to modulation of ripple power, and did not reveal a latent sensitivity of SWRs to cannabinoid receptor activation. Notably, CB1 receptor expression in the CA3 region was comparable between dorsal and ventral hippocampus. Conclusions: These findings demonstrate that spontaneous SWRs in hippocampal slices are robust to acute cannabinoid modulation despite strong CB₁ receptor expression. The intrinsic dorsoventral organization of hippocampal network dynamics persists under cannabinoid receptor activation, indicating that SWR generation is primarily based on local circuit properties rather than fast endocannabinoid signaling. This resistance has important implications for understanding how cannabinoids influence hippocampal function in vivo, suggesting that their cognitive and behavioral effects are likely mediated through modulation of large-scale network interactions rather than direct disruption of intrinsic SWR-generating mechanisms.