Essential roles of GABA transporter-1 in controlling rapid eye movement sleep and in increased slow wave activity after sleep deprivation.

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.

Requirement of regulated endocrine-specific protein-18 for development and expression of regulated endocrine-specific protein-18 isoform c in mice.

Regulated endocrine-specific protein-18 (RESP18) is distributed mainly in the peripheral endocrine and neuroendocrine tissues. The expression of RESP18 protein is regulated by physiological factors, such as blood glucose or dopaminergic drugs, but its functions remain unclear. In this study, to explore the biological functions of RESP18 in vivo, we generated RESP18 heterozygous deficient mice, and further found RESP18 was essential for embryonic development. In addition, we cloned a new isoform of mouse RESP18 by reverse transcription-polymerase chain reaction (RT-PCR), and denominated it as RESP18-c. Mouse RESP18-c, by skipping exon4 (43 bp in length), encodes a shorter protein of 120 amino acid residues. The distribution of RESP18-c mRNA is similar with that of RESP18 mRNA in the peripheral tissues and brains of mice.

Elevated interleukin-1beta induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine aggravating dopaminergic neurodegeneration in old male mice.

IL-1beta is a potent pro-inflammatory cytokine that regulates neuroinflammation during brain damage. The expression of IL-1beta has been reported to be elevated in the striatum and substantia nigra of patients with Parkinson's disease (PD). Moreover, greater prevalence of PD in men than in women is described previously. Here, by using a sensitive mice model in which the expression of luciferase reporter gene is under the control of human IL-1beta gene promoter, we examined IL-1beta gene expression pattern in vivo after subacute MPTP toxication in old male and female mice and found that MPTP elicited greater dopaminergic toxicity in old male than in female mice. Old male mice showed dramatically elevated luciferase signals in a flexuous manner at early period of time, meanwhile, the changes in female were more moderate. However, no significant difference in astroglial reaction was observed at later time point between sexes. In conclusion, the present study demonstrated that elevated IL-1beta gene expression at early period of time may be in part responsible for the DA neuron susceptibility to MPTP in old male mice.