Theta oscillations, epileptogenesis, and focal seizures in rodent models of mesial temporal lobe epilepsy

Abstract Theta oscillations (4–12 Hz) are a prominent network rhythm within hippocampal and parahippocampal structures. Driven by cholinergic and γ‐aminobutyric acidergic inputs originating from the medial septum, physiological theta gates network excitability to control spatial navigation, memory encoding, and sensorimotor integration during specific behavioral states. Theta rhythm also organizes the precise temporal binding of interneuron and principal cell firing via phase‐locking, a mechanism critical for synaptic plasticity and long‐term potentiation. Emerging evidence indicates that theta activity is disrupted in mesial temporal lobe epilepsy (MTLE). Here, we review recent studies on the role of theta oscillations during both the latent phase of epileptogenesis and the chronic epileptic phase in rodent models of MTLE. Specifically, we will focus on the paradox that subpopulations of inhibitory interneurons may pace theta oscillations to exert a compensatory inhibitory control on pathological network hyperexcitability, thus establishing an environment that favors ictogenesis. In conclusion, we propose that theta oscillations in an epileptic brain may serve as a defense mechanism that, unexpectedly, triggers focal seizures.