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Developmental decrease in parvalbumin‐positive neurons precedes increase in flurothyl‐induced seizure susceptibility in the Brd2 +/− mouse model of juvenile myoclonic epilepsy
Author(s) -
McCarthy Emily,
Shakil Faariah,
Saint Ange Patrick,
Morris Cameron Emily,
Miller James,
Pathak Shilpa,
Greenberg David A.,
Velíšková Jana,
Velíšek Libor
Publication year - 2020
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16499
Subject(s) - endocrinology , medicine , striatum , clonus , biology , neocortex , epilepsy , juvenile myoclonic epilepsy , neuroscience , dopamine
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. Significance A decrease in striatal PVA+ GABAergic neurons developmentally precedes the onset of increased seizure susceptibility and likely contributes to the expression of the syndrome.