Developmental decrease in parvalbumin‐positive neurons precedes increase in flurothyl‐induced seizure susceptibility in the Brd2^+/− mouse model of juvenile myoclonic epilepsy

Abstract

Objective: BRD2 is a human gene repeatedly linked to and associated with juvenile myoclonic epilepsy (JME). Here, we define the developmental stage when increased seizure susceptibility first manifests in heterozygous Brd2+/-mice, an animal model of JME. We wanted to determine (1) whether seizure susceptibility correlates with the proven decrease of γ-aminobutyric acidergic (GABAergic) neuron numbers and(2) whether the seizure phenotype can be affected by sex hormones. Methods: Heterozygous (Brd2+/-) and wild-type (wt) mice of both sexes were tested for flurothyl-induced seizure susceptibility at postnatal day 15 (P15; wt, n = 13; Brd2+/-, n = 20), at P30 (wt, n = 20; Brd2+/-, n = 20), and in adulthood (5-6 months of age; wt, n = 10; Brd2+/-, n = 12). We measured latency to clonic and tonic-clonic seizure onset (flurothyl threshold). We also compared relative density of parvalbumin-positive (PVA+) and GAD67+ GABA neurons in the striatum and primary motor (M1) neocortex of P15 (n = 6-13 mice per subgroup) and P30 (n = 7-10 mice per subgroup) mice. Additional neonatal Brd2+/-mice were injected with testosterone propionate (females) or formestane (males) and challenged with flurothyl at P30. Results: P15 Brd2+/-mice showed no difference in seizure susceptibility compared to P15 wt mice. However, even at this early age, Brd2+/-mice showed fewer PVA+ neurons in the striatum and M1 neocortex. Compared to wt, the striatum in Brd2+/mice showed an increased proportion of immature PVA+ neurons, with smaller cell bodies and limited dendritic arborization. P30 Brd2+/-mice displayed increased susceptibility to flurothyl-induced clonic seizures compared to wt. Both genotype and sex strongly influenced the density of PVA+ neurons in the striatum. Susceptibility to clonic seizures remained increased in adult Brd2+/-mice, and additionally there was increased susceptibility to tonic-clonic seizures. In P30 females, neonatal testosterone reduced the number of flurothyl-induced clonic seizures. How to cite this article: McCarthy E, Shakil F, Saint Ange P, et al. Developmental decrease in parvalbuminpositive neurons precedes increase in flurothyl-induced seizure susceptibility in the Brd2 +/− mouse model of juvenile myoclonic epilepsy. Epilepsia. 2020;61:892-902. https://doi.

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