title: Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility.
abstract: The most commonly reported precipitating factor for seizures is stress. However, the underlying mechanisms whereby stress triggers seizures are not yet fully understood. Here we demonstrate a potential mechanism underlying changes in neuronal excitability in the hippocampus following chronic stress, involving a shift in the reversal potential for GABA (EGABA) associated with a dephosphorylation of the potassium chloride co-transporter, KCC2. Mice subjected to chronic restraint stress (30min/day for 14 consecutive days) exhibit an increase in serum corticosterone levels which is associated with increased susceptibility to seizures induced with kainic acid (20mg/kg). Following chronic stress, but not acute stress, we observe a dephosphorylation of KCC2 residue S940, which regulates KCC2 cell surface expression and function, in the hippocampus. To determine the impact of alterations in KCC2 expression following chronic stress, we performed gramicidin perforated patch recordings to measure changes in EGABA and neuronal excitability of principal hippocampal neurons. We observe a depolarizing shift in EGABA in hippocampal CA1 pyramidal neurons after chronic stress. In addition, there is an increase in the intrinsic excitability of CA1 pyramidal neurons, evident by a shift in the input-output curve which could be reversed with the NKCC1 inhibitor, bumetanide. These data uncover a potential mechanism involving chronic stress-induced plasticity in chloride homeostasis which may contribute to stress-induced seizure susceptibility.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Georgina
authors.initials: G
authors.lastname: MacKenzie
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA. Electronic address: Jamie.Maguire@tufts.edu.
authors.forename: Jamie
authors.initials: J
authors.lastname: Maguire
mesh_terms: D000208:Acute Disease; D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D007608:Kainic Acid; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017966:Pyramidal Cells / Q000187:drug effects / Q000503:physiopathology; D012149:Restraint, Physical; D012640:Seizures / Q000503:physiopathology*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism; D013315:Stress, Psychological / Q000503:physiopathology*; D027981:Symporters / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D002034:Bumetanide; D003345:Corticosterone; D007608:Kainic Acid; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse
keywords: Chronic stress; Epilepsy; GABA; KCC2