RESUMO
UNLABELLED: 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. METHODS AND 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.
Assuntos
Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Hipocampo/fisiopatologia , Hipoglicemia/fisiopatologia , Potenciais da Membrana/fisiologia , Inibição Neural/fisiologia , Convulsões/fisiopatologia , Animais , Camundongos , Transmissão Sináptica/fisiologiaRESUMO
Electrophysiological oscillations are thought to create temporal windows of communication between brain regions. We show here that human cortical slices maintained in vitro can generate oscillations similar to those observed in vivo. We have characterized these oscillations using local field potential and whole-cell recordings obtained from neocortical slices acquired during epilepsy surgery. We confirmed that such neocortical slices maintain the necessary cellular and circuitry components, and in particular inhibitory mechanisms, to manifest oscillatory activity when exposed to glutamatergic and cholinergic agonists. The generation of oscillations was dependent on intact synaptic activity and muscarinic receptors. Such oscillations differed in electrographic and pharmacological properties from epileptiform activity. Two types of activity, theta oscillations and high gamma activity, uniquely characterized this model-activity not typically observed in animal cortical slices. We observed theta oscillations to be synchronous across cortical laminae suggesting a novel role of theta as a substrate for interlaminar communication. As well, we observed cross-frequency coupling (CFC) between theta phase and high gamma amplitude similar to that observed in vivo. The high gamma "bursts" generated by such CFC varied in their frequency content, suggesting that this variability may underlie the broadband nature of high gamma activity.