Allopregnanolone enhancement of GABAergic transmission in rat medial preoptic area neurons

Abstract

γ-Aminobutyric acid (GABA)-mediated transmission in the medial preoptic area (MPOA) of the hypothalamus plays an important role in functions such as sex steroid hormone dynamics and control of body temperature. The action of allopregnanolone, the primary metabolite of progesterone, on GABAergic transmission was investigated by employing patch clamp whole cell recording on acutely dissociated rat MPOA neurons with the functional connection of presynaptic terminals. Allopregnanolone enhanced spontaneous GABA release on the MPOA neurons and induced prolonged decay of miniature GABAergic-inhibitory postsynaptic currents (mIPSCs). The facilitation of GABA release from the presynaptic terminals by allopregnanolone disappeared in Ca2+-free extracellular solution. The presynaptic action of this neurosteroid was also blocked by bumetanide, a blocker of cation-Cl− cotransporters, and by removal of extracellular Na+. The results suggest that allopregnanolone enhances GABAergic transmission at the MPOA neurons by pre- and postsynaptic mechanisms. The enhancement of GABA release by allopregnanolone might require a high Cl− concentration in the presynaptic terminal maintained by Na+-dependent, bumetanide-sensitive mechanisms (e.g., Na+-K+-Cl− cotransporter) and might be mediated by Ca2+ influx into presynaptic terminal.

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

“…Allopregnanolone was also shown to prolong miniature inhibitory postsynaptic current (mIPSC) decay with no effect on mIPSC amplitudes in mPOA neurons acutely dissociated with adherent presynaptic terminals (Haage and Johansson, 1999: 50 nM; Uchida et al, 2002: 10 nM) or sIPSC amplitudes in dissociated medial preoptic nucleus (MPN) neurons (Haage et al, 2005; 1 μM). Allopregnanolone was also reported by Haage and colleagues (Haage and Johansson, 1999; 2 μM; Haage et al, 2005) and Uchida et al (2002;10 nM) to increase mIPSC and sIPSC frequency in dissociated mPOA/MPN neurons. In contrast to the lack of effect of allopregnanolone on PSC amplitudes noted in these studies, Jorge-Rivera et al (2000) reported that allopregnanolone and 3α-diol (both at 1 μM) potentiated the peak amplitude of spontaneous IPSCs (sIPSCs) recorded from the mPOA and the VMN of neonatal female rats.…”

“…In contrast to the lack of effect of allopregnanolone on PSC amplitudes noted in these studies, Jorge-Rivera et al (2000) reported that allopregnanolone and 3α-diol (both at 1 μM) potentiated the peak amplitude of spontaneous IPSCs (sIPSCs) recorded from the mPOA and the VMN of neonatal female rats. It is possible that acutely dissociated neurons with adherent presynaptic terminals respond differently to neurosteroid modulation (Haage and Johansson, 1999;Uchida et al, 2002;Haage et al, 2005) than do neurons in the intact slice (Jorge-Rivera et al, 2000).…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…This neurosteroid enhancement of mIPSCs from medial preoptic neurons has been confirmed by Uchida et al (2002). Sulfated neuroactive steroids can inhibit GABA release from hippocampal pyramidal cells by acting on a sigma receptor (Mtchedlishvili and Kapur, 2003).…”

Neurosteroids and GABAA Receptor Interactions: A Focus on Stress

“…Furthermore, it is plausible that the impact of an NO-induced increase in GABA release upon the inhibitory tone exerted on hypothalamic magnocellular neurons could be further amplified by neurosteroid potentiation of GABA A R function. Indeed, neurosteroids, such as 5α3α-THPROG, acting at presynaptic GABA A Rs, typically cause an increase in synaptic transmission (Haage et al, 2002; Uchida et al, 2002; Ruiz et al, 2010) due to the excitatory actions of GABA on presynaptic terminals (Kullmann et al, 2005; Szabadics et al, 2006; Trigo et al, 2008). Thus, following a stressful challenge, locally produced neurosteroids may potentially modulate synaptic transmission via actions at both pre- and postsynaptic GABA A Rs (Figure 2C).…”