Genetic and pharmacological modulation of giant depolarizing potentials in the neonatal hippocampus associates with increased seizure susceptibility

Authors

  • Ernesto Vargas,

    1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia
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  • Steven Petrou,

    1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia
    2. Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne, Australia
    3. Centre for Neural Engineering, University of Melbourne, Parkville, Melbourne, Australia
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  • Christopher A. Reid

    1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia
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C. Reid: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.  Email: careid@unimelb.edu.au

Key points

  • • Our earlier work established that seizure susceptibility in the GABAAγ2R43Q epilepsy mouse may be in part due to the developmental consequences of impaired GABA­A receptor function.
  • • Giant depolarizing potentials (GDP) are brain network activity that involve GABA transmission, and they are thought to be important for the wiring of the developing brain.
  • • The GABAAγ2R43Q epilepsy mutation may have an impact on this function.
  • • To test this, we measured GPD events in a mouse model with the human mutation and showed a significantly lower frequency of these events.
  • • We also reduced GDPs using a drug called bumetanide and showed an increased seizure susceptibility.
  • • Our data suggest that both genetic and pharmacological reductions in GDP expression can increase the likelihood of having a seizure when exposed to heat.

Abstract  The expression of Na+–K+–2Cl cotransporter (NKCC1) is responsible for high intracellular Cl resulting in the excitatory action of GABAA receptor activation in the developing brain. Giant depolarizing potentials (GDPs) are spontaneous network oscillations that involve GABAA receptors and are thought to be important in establishing neuronal circuit wiring. Earlier work established that seizure susceptibility in the GABAAγ2R43Q epilepsy mouse is impacted by developmental consequences of impaired GABAA receptor function. We investigated the potential mechanism of the developmental influence by recording GDPs in the CA3 pyramidal neurons from brain slices of the neonatal GABAAγ2R43Q mouse. Interestingly, the number of GPDs was significantly lower in slices from mutant mouse compared with wild-type control, suggesting an involvement in setting seizure susceptibility. To test this idea we blocked NKCC1 with bumetanide in neonatal mice and reduced the number of GDPs to a level similar to that seen in the mutant mice. We found that neonatal treatment with bumetanide resulted in a similar level of susceptibility to thermally induced seizures as described for the GABAAγ2R43Q mouse. These results provide evidence that a human GABAA receptor epilepsy mutation exerts a developmental influence by modulating the number of GDPs. It also draws attention to the potential risk of early treatment with bumetanide.

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