Abstract
GABA is the major inhibitory neurotransmitter in the mammalian central nervous system that has been strongly implicated in the regulation of sleep. GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA and regulates GABAergic transmission in the brain. However, the role of GAT1 in sleep-wake regulation remains elusive. In the current study, we characterized the spontaneous sleep-wake cycle and responses to sleep deprivation in GAT1 knock-out (KO) mice. GAT1 KO mice exhibited dominant theta-activity and a remarkable reduction of EEG power in low frequencies across all vigilance stages. Under baseline conditions, spontaneous rapid eye movement (REM) sleep of KO mice was elevated both during the light and dark periods, and non-REM (NREM) sleep was reduced during the light period only. KO mice also showed more state transitions from NREM to REM sleep and from REM sleep to wakefulness, as well as more number of REM and NREM sleep bouts than WT mice. During the dark period, KO mice exhibited more REM sleep bouts only. Six hours of sleep deprivation induced rebound increases in NREM and REM sleep in both genotypes. However, slow wave activity, the intensity component of NREM sleep was briefly elevated in WT mice but remained completely unchanged in KO mice, compared with their respective baselines. These results indicate that GAT1 plays a critical role in the regulation of REM sleep and homeostasis of NREM sleep.
Highlights
Brain function is based on an exquisite balance between excitatory and inhibitory neurotransmission
During NREM sleep, fast Fourier transform (FFT)-derived delta (0.5–4 Hz) power was greater than FFT-derived theta (6–10 Hz) power
During NREM-rapid eye movement (REM) transitions, Gamma-aminobutyric acid (GABA) transporter subtype 1 (GAT1) KO exhibited a sharp decrease in the FFT-derived delta power, increase of the FFT-derived theta power can be observed during REM sleep
Summary
Brain function is based on an exquisite balance between excitatory and inhibitory neurotransmission. Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian nervous system, where it actives GABAA, GABAB and GABAC receptors. Injection of the GABAA receptor (GABAAR) antagonists bicuculline or GABAzine into the sublaterodorsal nucleus (SLD), REM-on neurons induces a REM-like state in rats and cats [2,3,4]. Inactivation of the ventrolateral part of the periaqueductal gray (VLPAG) and the adjacent dorsal part of the deep mesencephalic reticular nuclei (dDpMe) REM-off neurons by muscimol (a GABAA agonist) application induces strong increases in REM sleep quantities [5,6]. The regions responsible for the generation of non-REM (NREM) sleep are located in the ventrolateral preoptic area (VLPO) and/or median preoptic nucleus (MnPO), where neurons showing sleep related c-Fos immunoreactivity are identified GABAergic [7,8]. Three generations of hypnotics are based on these GABAAR-mediated inhibitory processes
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