title: Hypoglycemia-induced alterations in hippocampal intrinsic rhythms: Decreased inhibition, increased excitation, seizures and spreading depression.
abstract: Seizures are the most common clinical presentation of severe hypoglycemia, usually as a side effect of insulin treatment for juvenile onset type 1 diabetes mellitus and advanced type 2 diabetes. We used the mouse thick hippocampal slice preparation to study the pathophysiology of hypoglycemia-induced seizures and the effects of severe glucose depletion on the isolated hippocampal rhythms from the CA3 circuitry.
  
  
  RESULTS
  Dropping the glucose perfusate concentration from the standard 10 mM to 1 mM produced epileptiform activity in 14/16 of the slices. Seizure-like events (SLEs) originated in the CA3 region and then spread into the CA1 region. Following the SLE, a spreading-depression (SD)-like event occurred (12/16 slices) with irreversible synaptic failure in the CA1 region (8/12 slices). CA3 SD-like events followed ~30 s after the SD-like event in the CA1 region. Less commonly, SD-like events originated in the CA3 region (4/12). Additionally, prior to the onset of the SLE in the CA3 area, there was decreased GABA correlated baseline SPW activity (bSPW), while there was increased large-amplitude sharp wave (LASW) activity, thought to originate from synchronous pyramidal cell firing. CA3 pyramidal cells displayed progressive tonic depolarization prior to the seizure which was resistant to synaptic transmission blockade. The initiation of hypoglycemic seizures and SD was prevented by AMPA/kainate or NMDA receptor blockade.
  
  
  CONCLUSIONS
  Severe glucose depletion induces rapid changes initiated in the intrinsic CA3 rhythms of the hippocampus including depressed inhibition and enhanced excitation, which may underlie the mechanisms of seizure generation and delayed spreading depression.
authors.affiliation: Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada; Division of Fundamental Neurobiology, TWRI, UHN, Toronto, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Florez
authors.affiliation: Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Lukankin
authors.affiliation: Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Sugumar
authors.affiliation: Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada.
authors.forename: R
authors.initials: R
authors.lastname: McGinn
authors.affiliation: Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada.
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Zhang
authors.affiliation: Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada; Division of Fundamental Neurobiology, TWRI, UHN, Toronto, Canada. Electronic address: carlen@uhnresearch.ca.
authors.forename: P L
authors.initials: PL
authors.lastname: Carlen
mesh_terms: D000818:Animals; D013181:Cortical Spreading Depression / Q000502:physiology*; D006624:Hippocampus / Q000503:physiopathology*; D007003:Hypoglycemia / Q000503:physiopathology*; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D009433:Neural Inhibition / Q000502:physiology*; D012640:Seizures / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology
keywords: Brain oscillations; Hippocampus; Hypoglycemia; In-vitro; In-vitro brain rhythms; Neuroglycopenia; Seizure; Spreading depression