Sex differences in estrogenic regulation of neuronal activity in neonatal cultures of ventromedial nucleus of the hypothalamus

Abstract

Estrogenic effects have been implicated in sexual differentiation of brain and behavior, in part by affecting neuronal activity in the ventromedial nucleus of the hypothalamus (VMN). We report here a remarkable sex difference in estrogenic regulation of neuronal activity in male vs. female neural networks. Spontaneous synaptic currents originating from a population of neurons were recorded in primary VMN cultures using the whole-cell patch-clamp technique. Treatment with 17␤-estradiol (E2, 10 nM) for 24 h induced opposite effects in the two sexes: the frequency of spontaneous synaptic events decreased significantly in neurons derived from males but increased in those from females. Interestingly, the 24-hour E2 effect was partially reversed by an acute application (5 min) of a second dose of E2 (10 nM), suggesting an interaction between extended (24-hr) and acute (5-min) effects of E2 in VMN neurons. To understand the underlying mechanism of this sexually dimorphic action of E2, we analyzed the E2 effect on GABAergic neurotransmission by recording miniature inhibitory postsynaptic currents. After 24-hour E2 treatment, both the amplitude and frequency of miniature inhibitory postsynaptic currents increased in neurons derived from males but decreased in those from females. These results suggest that E2-induced changes in GABAergic inhibition could at least partially explain E2 effects on neuronal activity. We conclude that E2 may have sexually dimorphic effects on the synaptic output of VMN neurons by modulating GABAergic neurotransmission.GABA ͉ sexual dimorphism ͉ steroid hormone E strogens (E) play important roles in a variety of neurobiological processes, including neural development and adult behaviors (1). The functional outcomes of these processes are coordinated with physiological events that are fundamentally different in males (() and females (&). These physiological events involve E interactions with nuclear E receptors (ERs), as well as interactions at several cellular levels, including signal transduction systems. One focus of these interactions is on hypothalamic neuronal activity. During a perinatal sensitive period, E exposure enhances neuronal excitability in the ( hypothalamus by affecting amino acid neurotransmitters, which might be a crucial mechanism in the process of masculinization of the ( brain (2). E plays a fundamental role in lordosis via actions in the ventromedial nucleus of the hypothalamus (VMN) (3, 4). Previous studies (5, 6) have demonstrated that an increase in VMN neuronal activity is a mechanism by which E acts through VMN to induce lordosis. However, the questions of exactly how E increases VMN neuronal activity and how sex differences might arise here remain to be elucidated.GABA plays an important role in VMN development (7), and GABAergic neurotransmission has been implicated in E's effects on several important functions, such as sexual differentiation during neural development (8) and lordosis behavior (9). E has been shown to affect many aspects of GABAergic transmission, ...

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