title: Microglia PACAP and glutamate: Friends or foes in seizure-induced autonomic dysfunction and SUDEP?
abstract: Seizure-induced cardiorespiratory autonomic dysfunction is a major cause of sudden unexpected death in epilepsy (SUDEP), and the underlying mechanism is unclear. Seizures lead to increased synthesis, and release of glutamate, pituitary adenylate cyclase activating polypeptide (PACAP), and other neurotransmitters, and cause extensive activation of microglia at multiple regions in the brain including central autonomic cardiorespiratory brainstem nuclei. Glutamate contributes to neurodegeneration, and inflammation in epilepsy. PACAP has neuroprotective, and anti-inflammatory properties, whereas microglia are key players in inflammatory responses in CNS. Seizure-induced increase in PACAP is neuroprotective. PACAP produces neuroprotective effects acting on microglial PAC1 and VPAC1 receptors. Microglia also express glutamate transporters, and their expression can be increased by PACAP in response to harmful or stressful situations such as seizures. Here we discuss the mechanism of autonomic cardiorespiratory dysfunction in seizure, and the role of PACAP, glutamate and microglia in regulating cardiorespiratory brainstem neurons in their physiological state that could provide future therapeutic options for SUDEP.
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2109 New South Wales, Australia; The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia.
authors.forename: Amol M
authors.initials: AM
authors.lastname: Bhandare
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2109 New South Wales, Australia; The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia.
authors.forename: Komal
authors.initials: K
authors.lastname: Kapoor
authors.affiliation: The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia; Department of Physiology, University of Sydney, Sydney 2006 New South Wales, Australia.
authors.forename: Melissa M J
authors.initials: MM
authors.lastname: Farnham
authors.affiliation: The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia; Department of Physiology, University of Sydney, Sydney 2006 New South Wales, Australia. Electronic address: paul.pilowsky@hri.org.au.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Pilowsky
mesh_terms: D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000378:metabolism; D003645:Death, Sudden; D004827:Epilepsy / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D012119:Respiration; D012640:Seizures / Q000378:metabolism
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018698:Glutamic Acid
keywords: Cardiorespiratory system; Glutamate; Inflammation; Microglia; PACAP; SUDEP; Seizure; Ventrolateral medulla