Sex dimorphism in seizure-controlling networks

Abstract

Males and females show a different predisposition to certain types of seizures in clinical studies. Animal studies have provided growing evidence for sexual dimorphism of certain brain regions, including those that control seizures. Seizures are modulated by networks involving subcortical structures, including thalamus, reticular formation nuclei, and structures belonging to the basal ganglia. In animal models, the substantia nigra pars reticulata (SNR) is the best studied of these areas, given its relevant role in the expression and control of seizures throughout development in the rat. Studies with bilateral infusions of the GABA(A) receptor agonist muscimol have identified distinct roles of the anterior or posterior rat SNR in flurothyl seizure control, that follow sex-specific maturational patterns during development. These studies indicate that (a) the regional functional compartmentalization of the SNR appears only after the third week of life, (b) only the male SNR exhibits muscimol-sensitive proconvulsant effects which, in older animals, is confined to the posterior SNR, and (c) the expression of the muscimol-sensitive anticonvulsant effects become apparent earlier in females than in males. The first three postnatal days are crucial in determining the expression of the muscimol-sensitive proconvulsant effects of the immature male SNR, depending on the gonadal hormone setting. Activation of the androgen receptors during this early period seems to be important for the formation of this proconvulsant SNR region. We describe molecular/anatomical candidates underlying these age- and sex-related differences, as derived from in vitro and in vivo experiments, as well as by [(14)C]2-deoxyglucose autoradiography. These involve sex-specific patterns in the developmental changes in the structure or physiology or GABA(A) receptors or of other subcortical structures (e.g., locus coeruleus, hippocampus) that may affect the function of seizure-controlling networks.

Keywords: Androgen receptor; Critical period; Dimorphism; Epilepsy; Estrogen receptor; GABA receptor; Hippocampus; Immature; KCC2; Locus Coeruleus; Rat; Seizures; Substantia nigra pars reticulata.

Fig. 1

Schematic representation of connections of male SNR in relation with seizure modulation. A: The SNR receives GABAergic afferents from the GP, as well as from the striatum; it also receives direct dopaminergic afferents from the SNpc, and glutamatergic projections from the STN. SNR, together with the globus pallidus internal (not shown in the figure) is the only output structure from the basal ganglia. It sends GABAergic efferents to its target structures: the thalamus, the SC and PPT. All of these three structures play a crucial role in seizure modulation. The cortex, thalamus and STN mainly send glutamatergic projections to their targets (dark red solid arrows); SNR, striatum and GP send GABAergic inhibitory efferents to their targets (orange dashed arrow); dotted gray arrows represent SNpc dopaminergic efferents. The PPT is formed by cholinergic neurons. Panels B and C show the effects of unilateral infusions of muscimol in the male SNR in terms of increased (red arrows) or decreased (blue arrows) [¹⁴C]2-deoxyglucose (2-DG) uptake in target regions (from Moshé et al., 1994, and unpublished observations from Moshé's Lab). The SNR sites are schematized as circles: the SNRa with an anticonvulsant effect of muscimol is depicted in white, while the proconvulsant site is in black. B: In adult male rats, unilateral muscimol infusion in the SNRp (where bilateral muscimol infusions are proconvulsant) increases 2-DG uptake in the ipsilateral GP and striatum; unilateral muscimol infusion into the SNRa (where bilateral muscimol infusions are anticonvulsant) decreases 2-DG uptake in the ipsilateral VM and GP, while it increases 2-DG uptake in the ipsilateral SC. C: in PN15 male rat SNR (where bilateral intranigral muscimol infusions are proconvulsant), unilateral muscimol infusions increase 2-DG uptake in the ipsilateral GP and striatum. Abbreviations: GP: lateral globus pallidus; PPT: pedunculopontine tegmental nucleus; SC: superior colliculus; SNpc: pars compacta of the substantia nigra; SNR: pars reticulata of the substantia nigra; SNRa: anterior part of SNR; SNRp: posterior part of SNR; STN: subthalamic nucleus; VM: ventro-medial thalamic nucleus.