title: Epigenetic Regulation of SNAP25 Prevents Progressive Glutamate Excitotoxicty in Hypoxic CA3 Neurons.
abstract: Exposure to global hypoxia and ischemia has been reported to cause neurodegeneration in the hippocampus with CA3 neurons. This neuronal damage is progressive during the initial phase of exposure but maintains a plateau on prolonged exposure. The present study on Sprague Dawley rats aimed at understanding the underlying molecular and epigenetic mechanisms that lead to hypoxic adaptation of CA3 neurons on prolonged exposure to a global hypoxia. Our results show stagnancy in neurodegeneration in CA3 region beyond 14 days of chronic exposure to hypobaria simulating an altitude of 25,000 ft. Despite increased synaptosomal glutamate and higher expression of NR1 subunit of NMDA receptors, we observed decrease in post-synaptic density and accumulation of synaptic vesicles at the pre-synaptic terminals. Molecular investigations involving western blot and real-time PCR showed duration-dependent decrease in the expression of SNAP-25 resulting in reduced vesicular docking and synaptic remodeling. ChIP assays for epigenetic factors showed decreased expression of H3K9Ac and H3K14Ac resulting in SNAP-25 promoter silencing during prolonged hypoxia. Administration of sodium butyrate, a non-specific HDAC inhibitor, during 21 days hypoxic exposure prevented SNAP-25 downregulation but increased CA3 neurodegeneration. This epigenetic regulation of SNAP-25 promoter was independent of increased DNMT3b expression and promoter methylation. Our findings provide a novel insight into epigenetic factors-mediated synaptic remodeling to prevent excitotoxic neurodegeneration on prolonged exposure to global hypobaric hypoxia.
authors.affiliation: Experimental Biology Division, Defence Institute of High Altitude Research, Defence Research and Development Organisation, c/o 56 APO, Leh-Ladakh, Jammu & Kashmir, Pin-901205, India.
authors.forename: Suryanarayan
authors.initials: S
authors.lastname: Biswal
authors.affiliation: Experimental Biology Division, Defence Institute of High Altitude Research, Defence Research and Development Organisation, c/o 56 APO, Leh-Ladakh, Jammu & Kashmir, Pin-901205, India.
authors.forename: Debashree
authors.initials: D
authors.lastname: Das
authors.affiliation: Department of Physiology, All India Institute of Medical Sciences, Bhubaneswar, India.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Barhwal
authors.affiliation: Experimental Biology Division, Defence Institute of High Altitude Research, Defence Research and Development Organisation, c/o 56 APO, Leh-Ladakh, Jammu & Kashmir, Pin-901205, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Anatomy, All India Institute of Medical Science, New Delhi, India.
authors.forename: Tapas Chandra
authors.initials: TC
authors.lastname: Nag
authors.affiliation: Department of Zoology, Banaras Hindu University, Varanasi, India.
authors.forename: Mahendra Kumar
authors.initials: MK
authors.lastname: Thakur
authors.affiliation: Experimental Biology Division, Defence Institute of High Altitude Research, Defence Research and Development Organisation, c/o 56 APO, Leh-Ladakh, Jammu & Kashmir, Pin-901205, India. drsunilhota@hotmail.com.
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Hota
authors.affiliation: Experimental Biology Division, Defence Institute of High Altitude Research, Defence Research and Development Organisation, c/o 56 APO, Leh-Ladakh, Jammu & Kashmir, Pin-901205, India.
authors.forename: Bhuvnesh
authors.initials: B
authors.lastname: Kumar
mesh_terms: D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic; D018698:Glutamic Acid / Q000633:toxicity*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D050825:Synaptosomal-Associated Protein 25; D020148:Butyric Acid; D018698:Glutamic Acid
keywords: Epigenetic regulation; Excitotoxicity; Hypoxia; SNAP-25; Synaptic remodeling