Sex-specific consequences of early life seizures

Abstract

Seizures are very common in the early periods of life and are often associated with poor neurologic outcome in humans. Animal studies have provided evidence that early life seizures may disrupt neuronal differentiation and connectivity, signaling pathways, and the function of various neuronal networks. There is growing experimental evidence that many signaling pathways, like GABAA receptor signaling, the cellular physiology and differentiation, or the functional maturation of certain brain regions, including those involved in seizure control, mature differently in males and females. However, most experimental studies of early life seizures have not directly investigated the importance of sex on the consequences of early life seizures. The sexual dimorphism of the developing brain raises the question that early seizures could have distinct effects in immature females and males that are subjected to seizures. We will first discuss the evidence for sex-specific features of the developing brain that could be involved in modifying the susceptibility and consequences of early life seizures. We will then review how sex-related biological factors could modify the age-specific consequences of induced seizures in the immature animals. These include signaling pathways (e.g., GABAA receptors), steroid hormones, growth factors. Overall, there are very few studies that have specifically addressed seizure outcomes in developing animals as a function of sex. The available literature indicates that a variety of outcomes (histopathological, behavioral, molecular, epileptogenesis) may be affected in a sex-, age-, region-specific manner after seizures during development. Obtaining a better understanding for the gender-related mechanisms underlying epileptogenesis and seizure comorbidities will be necessary to develop better gender and age appropriate therapies.

Keywords: Animal models; Development; Early life seizures; Epilepsy; GABA; Hippocampus; Sex differences; Status epilepticus; Substantia nigra.

Fig 1:

Sex-specific developmental changes in the direction of GABA_AR signaling are determined by cation chloride cotransporters. Panel A: Early in life, in most studied neurons, the intracellular Cl⁻ concentration is higher than in adults, due to the functional dominance of cation chloride cotransporters (CCCs) that import Cl⁻, like the Na⁺/K⁺/Cl⁻ cotransporter NKCC1, over cotransporters that export Cl⁻, like the K⁺/Cl⁻ cotransporter KCC2 (Plotkin et al., 1997; Rivera et al., 1999). As a result of this intracellular accumulation of Cl⁻, activation of GABA_AR triggers Cl⁻ efflux, neuronal depolarization that activates L-type voltage-sensitive calcium channels (L-VSCCs) or NMDA receptors (NRs) triggering intracellular calcium increases that eventually activate calcium-sensitive processes that are important in neuronal migration, proliferation, differentiation and synaptogenesis (Ben-Ari, 2002; Farrant and Kaila, 2007; Galanopoulou, 2008b). For example, GABA_AR-induced calcium rises activate the phosphorylation of certain transcriptional factors, like cAMP responsive element binding protein (CREB), and genes (e.g. KCC2). Furthermore, 17β-estradiol can downregulate KCC2 mRNA expression only in neurons that demonstrate depolarizing GABA_AR signaling. In certain sexually dimorphic brain regions, like the hypothalamus, CA1 pyramidal hippocampal neurons and substantia nigra, the developmental period when depolarizing GABA_AR signaling is observed is protracted, compared to same age females and this possibly contributes to the sex-specific differentiation of these regions. Panel B: During development, a gradual shift in the balance of these transporters from NKCC1 dominant to KCC2 dominant state is responsible for the switch of GABA_AR signaling from depolarizing to hyperpolarizing (Galanopoulou, 2008c; Plotkin et al., 1997; Rivera et al., 1999). The increased KCC2 and decline in NKCC1 activity reduce the inracellular Cl⁻ levels. Therefore, GABA_AR activation results in hyperpolarization. This strengthens the GABA_AR inhibition but also abolishes the transcriptional effects observed by depolarizing GABA_AR signaling. This Figure has been modified with permission from (Galanopoulou, 2008c).