Schuchmann, S. et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat. Med. 12, 817-823

Department of Biological and Environmental Sciences, University of Helsinki, Helsinki, Uusimaa, Finland
Nature Medicine (Impact Factor: 27.36). 08/2006; 12(7):817-23. DOI: 10.1038/nm1422
Source: PubMed


Febrile seizures are frequent during early childhood, and prolonged (complex) febrile seizures are associated with an increased susceptibility to temporal lobe epilepsy. The pathophysiological consequences of febrile seizures have been extensively studied in rat pups exposed to hyperthermia. The mechanisms that trigger these seizures are unknown, however. A rise in brain pH is known to enhance neuronal excitability. Here we show that hyperthermia causes respiratory alkalosis in the immature brain, with a threshold of 0.2-0.3 pH units for seizure induction. Suppressing alkalosis with 5% ambient CO2 abolished seizures within 20 s. CO2 also prevented two long-term effects of hyperthermic seizures in the hippocampus: the upregulation of the I(h) current and the upregulation of CB1 receptor expression. The effects of hyperthermia were closely mimicked by intraperitoneal injection of bicarbonate. Our work indicates a mechanism for triggering hyperthermic seizures and suggests new strategies in the research and therapy of fever-related epileptic syndromes.

    • "Moreover, Na V 1.1 channels may be expressed in cortical interneurons other than PV-and SST-positive cells, and these other interneuron subtypes may play an important role in the pathogenesis of SMEI. Finally, another possibility is that the abnormalities in membrane excitability observed in the slice experiments become apparent only under certain stressful conditions such as hyperthermia-induced alkalosis (Schuchmann et al. 2006Schuchmann et al. , 2011). Future experiments will be crucial to test these hypotheses. "
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    ABSTRACT: Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a(-/+) mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the main pathological mechanism underlying SMEI. Yet, the functional consequences of this interneuronal dysfunction at the circuit level in vivo are unknown. Here, we investigated whether Scn1a(-/+) mice showed alterations in cortical network function. We found that various forms of spontaneous network activity were similar in Scn1a(-/+) during the pre-epileptic period compared with wild-type (WT) in vivo. Importantly, in brain slices from Scn1a(-/+) mice, the excitability of parvalbumin (PV) and somatostatin (SST) interneurons was reduced, epileptiform activity propagated more rapidly, and complex synaptic changes were observed. However, in vivo, optogenetic reduction of firing in PV or SST cells in WT mice modified ongoing network activities, and juxtasomal recordings from identified PV and SST interneurons showed unaffected interneuronal firing during spontaneous cortical dynamics in Scn1a(-/+) compared with WT. These results demonstrate that interneuronal hypoexcitability is not observed in Scn1a(-/+) mice during spontaneous activities in vivo and suggest that additional mechanisms may contribute to homeostatic rearrangements and the pathogenesis of SMEI.
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    • "Full - band ( Fb ) ( DC ) EEG recordings were performed as described previously ( Schuchmann et al . , 2006 ) . Electrodes were implanted at P5 – P6 under isoflurane ( 1 . 5 – 2% ) . Two non - injected control rats were implanted at P8 . Custom - made AgCl electrode arrays ( with ca 0 . 5 mm uninsulated and chlorided tips ) were inserted into middle - deep layers of the S1 limb area ( 0 . 5 mm posterior to 0 . 5 mm anterior from bregma ; medi"

    Full-text · Dataset · Dec 2015
    • "neural network activity . The fact that respiratory CO 2 - regulatory regimes are able to interrupt sei - zure activity ( Schuchmann et al . , 2006 ) further - more accentuates the relevance of bidirectional homeostatic adaptive regulation of KCC2 expres - sion as a function of neuronal carbonic anhy - drase expression . However , the homeostatic machinery may also fail in disease conditions . Actually , there is increasing evidence that supports a critical role for the axonal and "

    No preview · Chapter · Oct 2015
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