Ripples in Time and Space Regulate Epileptic Firing in the Hippocampus

Collapsing Perisomatic Inhibition Leads to Epileptic Fast-Ripple Oscillations Caused by Pseudosynchronous Firing of CA3 Pyramidal Neurons Schlingloff D, Freund TF, Hangya B, Gulyás A. J Neurosci . 2025;12;45:e0500252025 Diverse network oscillations, thought to represent different information processing modes of cortical networks, are accompanied by synchronous neuronal activity at various temporal scales. Sharp wave-associated ripple oscillations, supporting memory consolidation in the hippocampus, are among the fastest physiological oscillations characterized by strong interneuronal synchrony. In contrast, when hippocampal activity turns epileptic, pathological fast-ripple oscillations appear. The distinction of the two oscillations is diagnostically relevant; however, how differential mechanisms of the same network generate the two activities is not well understood. Here, we addressed this question using an in vitro hippocampal model that allowed targeted recording of cell types and local pharmacological manipulations in mice of either sex. We showed that inhibition did not contribute to current and rhythm generation of fast-ripples, unlike physiological ripple oscillations. Instead, pathological fast-ripples emerged when perisomatic inhibition from parvalbumin-expressing basket cells collapsed and depended on the quasi-simultaneous onset of stereotypical pyramidal cell (PC) bursts, leading to pseudosynchrony. This was accompanied by a loss of spatial coherence. In epileptogenic conditions, deep CA3 PCs selectively ramped up their burst activity before fast-ripple onset, while normally nonbursting superficial PCs acquired burst capability. These results point to PC pseudosynchrony as the underlying mechanism of fast-ripples, with differential contribution of known PC types.