Integration of the CA2 region in the hippocampal network during epileptogenesis

Abstract

The CA2 pyramidal cells are mostly resistant to cell death in mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis, but they are aberrantly integrated into the epileptic hippocampal network via mossy fiber sprouting. Furthermore, they show increased excitability in vitro in hippocampal slices obtained from human MTLE specimens or animal epilepsy models. Although these changes promote CA2 to contribute to epileptic activity (EA) in vivo, the role of CA2 in the epileptic network within and beyond the sclerotic hippocampus is still unclear. We used the intrahippocampal kainate mouse model for MTLE, which recapitulates most features of the human disease including pharmacoresistant epileptic seizures and hippocampal sclerosis, with preservation of dentate gyrus (DG) granule cells and CA2 pyramidal cells. In vivo recordings with electrodes in CA2 and the DG showed that EA occurs at high coincidence between the ipsilateral DG and CA2 and current source density analysis of silicon probe recordings in dorsal ipsilateral CA2 revealed CA2 as a local source of EA. Cell‐specific viral tracing in Amigo2‐icreERT2 mice confirmed the preservation of the axonal projection from ipsilateral CA2 pyramidal cells to contralateral CA2 under epileptic conditions and indeed, EA propagated from ipsi‐ to contralateral CA2 with increasing likelihood with time after KA injection, but always at lower intensity than within the ipsilateral hippocampus. Furthermore, we show that CA2 presents with local theta oscillations and like the DG, shows a pathological reduction of theta frequency already from 2 days after KA onward. The early changes in activity might be facilitated by the loss of glutamic acid decarboxylase 67 (Gad67) mRNA‐expressing interneurons directly after the initial status epilepticus in ipsi‐ but not contralateral CA2. Together, our data highlight CA2 as an active player in the epileptic network and with its contralateral connections as one possible router of aberrant activity.

RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus

“…Recent evidence has supported a role for hippocampal area CA2 in modulating hippocampal network activity and seizure generation (Boehringer et al, 2017; Kilias et al, 2022; Whitebirch et al, 2022). Because RGS14 is highly and selectively expressed within area CA2 where it reduces neuronal excitability and inhibits long-term potentiation at CA3-CA2 excitatory synapses (Lee et al, 2010), we explored whether loss of RGS14 (RGS14 KO) altered hippocampal seizure activity.…”

“…Our group and others have shown that RGS14 is integral for area CA2 pyramidal cell (PC) signaling and function (Montanez-Miranda et al, 2022). Based on recent reports of the protective capacity of RGS14 in peripheral tissue (Li et al, 2016; Zhang et al, 2022) and the newly appreciated contribution of area CA2 in TLE (Freiman et al, 2021; Haussler et al, 2016; Kilias et al, 2022; Whitebirch et al, 2022; Wittner et al, 2009), we hypothesized that RGS14 may serve a protective role in area CA2 following seizure insult. Here, we show that loss of RGS14 sensitizes mice to the behavioral effects of KA-SE demonstrated by expedited entry into SE and mortality.…”

“…In human and animal models of temporal lobe epilepsy (TLE), the hippocampus is subjected to neuropathological changes including hyperexcitability, neuroinflammation, and neurodegeneration. Importantly, CA2 has been shown to modulate excitatory/inhibitory balance of the hippocampus (Boehringer et al, 2017) and contribute to hippocampal epileptiform activity in human TLE and mouse models of TLE (Kilias et al, 2022; Whitebirch et al, 2022). Recent reports show CA2 becomes enlarged and receives sprouting mossy fiber connections (another hallmark of epilepsy) in mouse models of SE and patients with TLE (Freiman et al, 2021; Haussler et al, 2016), leading to the hypothesis that CA2 survives to maintain the hippocampal network while also promoting the development of TLE.…”

Introduction to the special issue on: A new view of hippocampal area CA2

“…Additionally, these mice have facilitated the study of CA2 in the context of seizures, as reported here in a research article by Häussler and colleagues (Kilias et al, 2023). Given CA2's position within the hippocampal circuit, and its apparent resistance to cellular injury (Leranth & Ribak, 1991;Sloviter et al, 1991), it is clear that CA2 likely plays a central role in the pathological activity seen in individuals with epilepsy and understanding that role will be critical in developing more effective treatment strategies (Boehringer et al, 2017;Häussler et al, 2016;Whitebirch et al, 2022).…”

Hippocampal area CA2 controls seizure dynamics, interictal EEG abnormalities and social comorbidity in mouse models of temporal lobe epilepsy

“…5 This resistance of the DG and CA2 neurons to neuronal loss in TLE has been proposed to make these areas critical to seizure propagation through the epileptic hippocampus. [6][7][8] However, relatively few studies have directly tested the idea that area CA2 regulates seizures in TLE.…”