Altered Hippocampal Activation in Seizure-Prone CACNA2D2 Knock-out Mice

• Published in: eNeuro Vol. 11; no. 5; p. ENEURO.0486-23.2024
• Main Authors: Danis, Alyssa B, Gallagher, Ashlynn A, Anderson, Ashley N, Isakharov, Arielle, Beeson, Kathleen A, Schnell, Eric
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 01-05-2024
• Subjects: Animals; Calcium Channels - genetics; Calcium Channels - metabolism; Convulsants - toxicity; Disease Models, Animal; Hippocampus - metabolism; Hippocampus - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Negative Results; Neurons - metabolism; Neurons - pathology; Pentylenetetrazole; Proto-Oncogene Proteins c-fos - metabolism; Seizures - genetics; Seizures - metabolism; Seizures - pathology; epilepsy; dentate gyrus; hippocampus; calcium channels; alpha-2-delta
• ISSN: 2373-2822; 2373-2822
• DOI: 10.1523/ENEURO.0486-23.2024

The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c
and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and α2δ-2 knock-out (
KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c-
and
expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 h after handling-associated convulsions, KO mice had fewer c-
-positive cells but dramatically increased
expression in the dentate gyrus compared with WT mice. After administration of a subthreshold pentylenetetrazol dose, however, KO mice dentate had significantly more c-
expression compared with WT mice. Other histopathological markers of TLE in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar between WT and KO mice, apart from a small but statistically significant increase in hilar mossy cell density, opposite to what is typically found in mice with TLE. This suggests that the differences in seizure-associated dentate gyrus function in the absence of α2δ-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.