GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter of the mature central nervous system. The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl- gradients, which are generated by cation-Cl- co-transporters. An accumulation of Cl- by the Na+-K+-2Cl- co-transporter (NKCC1) increases the intracellular Cl- concentration ([Cl-]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl--extruder KCC2, which is a neuron-specific K+-Cl- co-transporter, with or without downregulation of NKCC1, results in low [Cl-]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl- homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases) in [Cl-]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including BDNF, insulin-like growth factor, and CFTR. Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl- homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors SPAK-OSR1. In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na+ and K+ ions, topographical interaction with the Na+-K+ ATPase and its modulators such as creatine kinase should modulate functions of Cl- transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl- transporters may also play a pivotal role in the development of Cl- homeostasis.

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.

Homozygous knockin mice reveal critical regulation of the neuronal channel KCC2 in synaptic development.

Objective: A pathological excitatory action of the major inhibitory neurotransmitter γ‐aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl⁻ importer NKCC1 with bumetanide is expected to reduce the neuronal intracellular Cl⁻ concentration ([Cl⁻]_i) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy were conducted. Although NKCC1 is expressed in both neurons and glial cells, an involvement of glial NKCC1 in seizures has not yet been reported. Astrocytes maintain high [Cl⁻]_i with NKCC1, and this gradient promotes Cl⁻ efflux via the astrocytic GABA_A receptor (GABA_AR). This Cl⁻ efflux buffers the synaptic cleft Cl⁻ concentration to maintain the postsynaptic Cl⁻ gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during seizure. In this study, we investigated the function of astrocytic NKCC1 in modulating the postsynaptic action of GABA in acute seizure models.Methods: We used the astrocyte‐specific conditional NKCC1 knockout (AstroNKCC1KO) mice. The seizurelike events (SLEs) in CA1 pyramidal neurons were triggered by tetanic stimulation of stratum radiatum in acute hippocampus slices. The SLE underlying GABA_AR‐mediated depolarization was evaluated by applying the GABA_AR antagonist bicuculline. The pilocarpine‐induced seizure in vivo was monitored in adult mice by the Racine scale. The SLE duration and tetanus stimulation intensity threshold and seizure behavior in AstroNKCC1KO mice and wild‐type (WT) mice were compared.Results: The AstroNKCC1KO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABA_AR‐mediated depolarization underlying the SLEs, accompanied by higher Racine‐scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCC1KO mice (which still express neuronal NKCC1), but not in the WT, both in vitro and in vivo.Significance: Astrocytic NKCC1 inhibits GABA‐mediated excitatory action during seizures, whereas neuronal NKCC1 has the converse effect, suggesting opposing actions of bumetanide on these cells.

As an important neurotransmitter, glutamate acts in over 90% of excitatory synapses in the human brain. Its metabolic pathway is complicated, and the glutamate pool in neurons has not been fully elucidated. Tubulin polyglutamylation in the brain is mainly mediated by two tubulin tyrosine ligase-like (TTLL) proteins, TTLL1 and TTLL7, which have been indicated to be important for neuronal polarity. In this study, we constructed pure lines of Ttll1 and Ttll7 knockout mice. Ttll knockout mice showed several abnormal behaviors. Matrix-assisted laser desorption/ionization (MALDI) Imaging mass spectrometry (IMS) analyses of these brains showed increases in glutamate, suggesting that tubulin polyglutamylation by these TTLLs acts as a pool of glutamate in neurons and modulates some other amino acids related to glutamate.

Taurine (2-aminoethanesulfonic acid) plays an important role in various physiological functions and is abundant in the brain and skeletal muscle. Extracellular taurine is an endogenous agonist of gamma-aminobutyric acid type A and glycine receptors. Taurine actively accumulates in cells via the taurine transporter (TauT). Adult taurine-knockout (TauT^−/−) mice exhibit lower body weights and exercise intolerance. To further examine the physiological role of taurine, we examined the effect of its depletion on mouse behavior, startle responses, muscular endurance, and body weight during development from postnatal day 0 (P0) until P60. In the elevated plus maze test, TauT^−/− mice showed decreased anxiety-like behavior. In addition, TauT^−/− mice did not show a startle response to startle stimuli, suggesting they have difficulty hearing. Wire-hang test revealed that muscular endurance was reduced in TauT^−/− mice. Although a reduction of body weight was observed in TauT^−/− mice during the developmental period, changes in body weight during 60% food restriction were similar to wild-type mice. Collectively, these results suggest that taurine has important roles in anxiety-like behavior, hearing, muscular endurance, and maintenance of body weight.