Enhanced excitability of the hippocampal CA2 region and its contribution to seizure generation in a mouse model of temporal lobe epilepsy

Abstract

The hippocampal CA2 region, an area important for social memory, has been suspected to play a role in temporal lobe epilepsy (TLE) because of its resistance to the degeneration observed in neighboring CA1 and CA3 regions in both human and rodent models of TLE. However, little is known about whether alterations in CA2 properties serve to promote seizure generation or propagation. Here we have used the pilocarpine-induced status epilepticus (PILO-SE) model of TLE to explore the role of CA2. Ex vivo electrophysiological recordings from acute hippocampal slices revealed a set of coordinated changes that enhance CA2 intrinsic excitability, reduce CA2 local inhibitory input, and increase CA2 excitatory output to its major CA1 synaptic target. Moreover, selective silencing of CA2 pyramidal cells using a chemogenetic approach caused a significant decrease in the frequency of spontaneous seizures. These findings provide the first evidence that CA2 actively contributes to TLE seizure activity and may thus be a promising therapeutic target.

Reduced cholecystokinin-expressing interneuron input contributes to disinhibition of the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

“…We recently found that in the pilocarpine-induced status epilepticus mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al, 2022). In the present study we explored the basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches.…”

“…Our goal here was to provide a detailed quantitative investigation into how the various hippocampal cornu ammonis regions (CA1, CA2 and CA3) are affected in the PILO-SE mouse model of TLE, with particular attention to the mechanisms underlying our previously characterized loss of synaptic inhibitory drive onto CA2 pyramidal cells (Whitebirch et al, 2022). In our previous and current study, we characterized the alterations in the electrophysiological properties of CA2 neurons in acute hippocampal slices from PILO-SE mice that were F1 hybrids from a cross between C57BL/6J and 129S1/SvlmJ mouse lines.…”

“…CA2 pyramidal neurons (PNs) are centrally located within the hippocampal network and receive exceptionally strong entorhinal cortex (EC) input, thus acting as the central node in a powerful disynaptic circuit linking the entorhinal cortex directly to CA1 (Chevaleyre & Siegelbaum, 2010; Cui, Gerfen, & Young, 2013; Hitti & Siegelbaum, 2014; Kohara et al, 2014; Leroy et al, 2017; Sun et al, 2017). CA2 PNs also receive direct input from dentate gyrus (DG) granule cell mossy fibers (Kohara et al, 2014; Whitebirch et al, 2022), and CA2 PN local axonal collaterals contribute to an excitatory recurrent network throughout the CA2 and CA3 subfields (Cui et al, 2013; Hitti & Siegelbaum, 2014; Ishizuka, Weber, & Amaral, 1990; Kohara et al, 2014; Li, Somogyi, Ylinen, & Buzsáki, 1994; Okamoto & Ikegaya, 2018; Tamamaki, Abe, & Nojyo, 1988; Whitebirch et al, 2022). Among the hippocampal subfields CA2 contains the greatest density of inhibitory interneurons, including a population of parvalbumin-expressing (PV+) interneurons with distinct anatomical and physiological properties (Botcher, Falck, Thomson, & Mercer, 2014; Mercer, Eastlake, Trigg, & Thomson, 2012; Mercer, Trigg, & Thomson, 2007).…”

“…Indeed, in the pilocarpine-induced status epilepticus (PILO-SE) model of TLE in mice we recently found that chemogenetic inhibition of CA2 PNs in vivo significantly reduced the frequency of spontaneous recurring convulsive seizures (Whitebirch et al, 2022). Acute hippocampal slice electrophysiology revealed multiple alterations to the cells and circuitry of the CA2 subfield, including a significant impairment to feedforward inhibition that may facilitate the emergence and propagation of epileptiform activity (Whitebirch et al, 2022).…”

“…Indeed, in the pilocarpine-induced status epilepticus (PILO-SE) model of TLE in mice we recently found that chemogenetic inhibition of CA2 PNs in vivo significantly reduced the frequency of spontaneous recurring convulsive seizures (Whitebirch et al, 2022). Acute hippocampal slice electrophysiology revealed multiple alterations to the cells and circuitry of the CA2 subfield, including a significant impairment to feedforward inhibition that may facilitate the emergence and propagation of epileptiform activity (Whitebirch et al, 2022). Here, we used electrophysiological and immunohistochemical approaches to explore the mechanisms underlying this inhibitory impairment and found that PILO-SE was associated with alterations to interneuronal populations that may compromise inhibitory control of CA2 excitability in epileptic mice.…”