ABSTRACT
BACKGROUND: Maintaining gamma-aminobutyric acidergic (GABAergic) inhibition in the amygdala within a physiological range is critical for the appropriate expression of emotions such as fear and anxiety. The synaptic GABA type A receptor (GABAAR) is generally known to mediate the primary component of amygdala inhibition and prevent inappropriate expression of fear. However, little is known about the contribution of the extrasynaptic GABAAR to amygdala inhibition and fear. METHODS: By using mice expressing green fluorescent protein in interneurons (INs) and lacking the δ subunit-containing GABAAR (GABAA(δ)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABAA(δ)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: In sharp contrast to the established role of synaptic GABAAR in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABAA(δ)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABAA(δ)R. The disinhibition arose from IN-specific expression of GABAA(δ)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABAA(δ)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABAA(δ)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear. CONCLUSIONS: Our findings suggest that GABAA(δ)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABAA(δ)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion.
Subject(s)
Amygdala/physiology , Fear/physiology , Neural Inhibition/physiology , Receptors, GABA-A/physiology , Animals , Conditioning, Psychological/physiology , Excitatory Postsynaptic Potentials/physiology , Inhibitory Postsynaptic Potentials/physiology , Interneurons/physiology , Long-Term Potentiation/physiology , Male , Mice , Mice, Knockout , Mice, Transgenic , Receptors, GABA-A/biosynthesisABSTRACT
Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share specific molecular mechanisms, and agents with proven efficacy in one may be useful against the other. The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has similar properties to GLP-1 and is currently in clinical use for T2DM treatment. Thus, this study was designed to characterize the effects of exendin-4 on the impairment of learning and memory induced by amyloid protein (Aß) and its probable molecular underlying mechanisms. The results showed that (1) intracerebroventricular (i.c.v.) injection of Aß1-42 resulted in a significant decline of spatial learning and memory of rats in water maze tests; (2) pretreatment with exendin-4 effectively and dose-dependently protected against the Aß1-42-induced impairment of spatial learning and memory; (3) exendin-4 treatment significantly decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl2 in Aß1-42-induced Alzheimer's rats. The vision and swimming speed of the rats among all groups in the visible platform tests did not show any difference. These findings indicate that systemic pretreatment with exendin-4 can effectively prevent the behavioral impairment induced by neurotoxic Aß1-42, and the underlying protective mechanism of exendin-4 may be involved in the Bcl2, Bax and caspase-3 pathways. Thus, the application of exendin-4 or the activation of its signaling pathways may be a promising strategy to ameliorate the degenerative processes observed in AD.
Subject(s)
Amyloid beta-Peptides/adverse effects , Glucagon-Like Peptide 1/agonists , Maze Learning/drug effects , Memory/drug effects , Peptides/pharmacology , Spatial Learning/drug effects , Venoms/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Exenatide , Male , Memory/physiology , Rats , Rats, Sprague-Dawley , Spatial Learning/physiologyABSTRACT
Heat shock protein 72 (HSP72) and glycoprotein 96 (gp96) are highly expressed in cancer tissues. Recent studies indicate the possible roles of HSP72 and gp96 in the development and progression of gastric carcinomas but detailed information is still ambiguous. In this study, we investigated the correlation between clinicopathology and expression of HSP72 and gp96 in human gastric carcinoma. The expression of HSP72 and gp96 was studied in 60 human gastric carcinomas with or without metastasis as well as in mucous membrane adjacent to cancers by way of immunohistochemistry. HSP72 immunoreactivities were detected in 54 of 60 primary tumors (90.0%) and in 22 of 60 mucous membranes adjacent to cancers (36.7%). Likewise, gp96 immunoreactivities were detected in 49 cases of gastric carcinoma (81.7%) and in 15 samples of mucous membrane adjacent to cancer (25.0%). Both HSP72 and gp96 were stained in cytoplasm. HSP72 and gp96 expression in colonic carcinomas with metastasis was significantly higher than those with non-metastasis (p < 0.05). The results indicate that there exists a significant correlation between the expression of HSP72 and gp96 and the progression of gastric carcinomas. The high-level expression of HSP72 and gp96 may be used as diagnostic or prognostic markers for gastric carcinoma.
