Hollnagel, J.-O. | bioRxiv Science

bioRxiv2022

Status epilepticus induces chronic silencing of burster and dominance of regular firing neurons during sharp wave-ripples in the mouse subiculum

Sharp wave-ripples (SWRs) are hippocampal oscillations associated with memory consolidation. The subiculum, as the hippocampal output structure, ensures that hippocampal memory representations are transferred correctly to the consolidating neocortical regions. Because patients with temporal lobe epilepsy often develop memory deficits, we hypothesized that epileptic networks may disrupt subicular SWRs. We therefore investigated the impact of experimentally induced status epilepticus (SE) on subicular SWRs and contributing pyramidal neurons using electrophysiological recordings in mouse hippocampal slices. Subicular SWRs expressed hyperexcitable features post-SE, including increased ripple and unit activity. While regular firing neurons normally remain silent during SWRs, selective disinhibition recruited more regular firing neurons for action potential generation during SWRs post-SE. By contrast, burster neurons generated fewer action potential bursts during SWRs post-SE. Furthermore, altered timing of postsynaptic and action potentials suggested distorted neuronal recruitment during SWRs. Distorted subicular SWRs may therefore impair information processing and memory consolidation in epilepsy.

neuroscience↗

bioRxiv2021

Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability arising from the loss of fragile X mental retardation protein (FMRP), a protein that plays a central role in neuronal function and plasticity. FXS patients show sensory hypersensitivity, hyperarousal and hippocampus-dependent learning deficits that can be recapitulated in the FMR1 KO mice. Enhanced metabotropic glutamate receptor (mGluR) signaling and muscarinic acetylcholine receptor (mAChR) signaling in the FMR1 KO mouse are implicated as the primary causes of the disease pathogenesis. Furthermore, glutamatergic kainate receptor (KAR) function is reduced in the cortex of the FMR1 KO mice. Of note, activation of these signaling pathways leads to slow gamma-range oscillations in the hippocampus in vitro and abnormal gamma oscillations have been reported in FMR1 KO mice and patients with FXS. Thus, we hypothesized that aberrant activation of these receptors leads to the observed gamma oscillopathy. We recorded gamma oscillations induced by either cholinergic agonist carbachol (CCh), mGluR1/5 agonist Dihydroxyphenylglycine (DHPG) or ionotropic glutamatergic agonist KA from the hippocampal CA3 in WT and FMR1 KO mice in vitro. We show a specific increase in the power of DHPG and CCh-induced gamma oscillations and reduction in the synchronicity of gamma oscillations induced by KA. We further elucidate an aberrant spiking activity during CCh-induced and kainate-induced gamma oscillations which may underlie the altered gamma oscillation synchronization in the FMR1 KO mice. Last, we also noted a reduced incidence of spontaneously-occurring hippocampal sharp wave-ripple events. Our study provides further evidence for aberrant hippocampal rhythms in the FMR1 KO mice and identifies potential signaling pathways underlying gamma band oscillopathy in FXS.

neuroscience↗