The role of GABA in the regulation of GnRH neurons

Abstract

Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA) has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction.

Keywords: GABA; GnRH neuron; KCC2; LH surge; NKCC1.

Figure 1

Excitatory action of GABA on rat GnRH neurons. (A) Representative [Ca²⁺]_i response to 100 μM GABA. Most GnRH neurons showed [Ca²⁺]_i increase in response to GABA. Some GnRH neurons did not respond to GABA. Some GnRH neurons showed [Ca²⁺]_i decrease in response to GABA. (B) Muscimol (100 μM), a GABA_A receptor agonist, increased [Ca²⁺]_i in GnRH neurons. (C) Bicuculline (100 μM), a GABA_A receptor antagonist, inhibited the [Ca²⁺]_i increase induced by GABA. (D) GABA-induced [Ca²⁺]_i increase was inhibited in Ca²⁺-free solution. (E) Bumetanide (100 μM), a blocker of NKCC1, reduced the GABA-induced [Ca²⁺]_i increase. Muscimol and GABA were applied as indicated with horizontal bars. Bicuculline, Ca²⁺-free solution, and bumetanide were applied as indicated with open bars (Originally published in Watanabe et al., 2009a).

Figure 2

The intracellular Cl⁻ concentration determines the polarity of GABA response. The GABA action is excitatory in immature neurons because [Cl⁻]_i is high, owing to high levels of the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC1), which mediates inward transport of Cl⁻, and to low levels of the K⁺-Cl⁻ cotransporter (KCC2), which excludes Cl⁻ from the cell. In most neurons, the GABA response switches from excitation to inhibition during early postnatal development, due to the developmental decrease of the NKCC1 and increase of the KCC2. However, even in the mature neurons, neuronal damage down regulates the KCC2 and elevated Cl⁻ concentration shifts GABA response from hyperpolarization to depolarization, occasionally excitation. Most GnRH neurons show the unusual characteristic of being excited by GABA in the adult brain.