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Trial Lecture – time and place
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Adjudication committee
- First opponent: Group Leader Ulrike Hedrich-Klimosch, Hertie Institute for Clinical Brain Research, Germany
- Second opponent: Senior Research Associate Nikolaus Maier, Charité Berlin, Germany
- Third member and chair of the evaluation committee: Professor Mahmood Amiry-Moghaddam, University of Oslo
Chair of the Defence
Associate professor Kay Schink, University of Oslo
Principal Supervisor
Researcher Fabian C. Roth, University of Oslo
Summary
Disruption of the balance between excitation and inhibition in brain circuits is a core mechanism in epilepsy. People with Dravet syndrome (DS), an epileptic encephalopathy, suffer from seizures and persistent cognitive problems, but the underlying network mechanisms are still poorly understood. This thesis studied how two ion channels, NaV1.1 and Kir4.1, shape neuronal excitability and hippocampal sharp wave ripple (SPW-R) oscillations in mouse models of genetic epilepsy.
In Paper I, I examined Scn1a+/– mice, a DS model with NaV1.1 haploinsufficiency predominantly in interneuron axons. Hippocampal field recordings combined with whole cell somatic and proximal axonal recordings from parvalbumin expressing interneurons (PV-INs) showed that in young adult Scn1a+/– mice, but not in juvenile Scn1a+/– mice, ripple frequency was reduced compared with control mice, and SPW-R evoked action potentials (APs) were smaller, broader and slower. Inhibitory synaptic input to CA1 pyramidal cells and PV-INs displayed a reduced temporal correlation with ripple cycles, consistent with an increased excitatory drive onto PV-INs. Direct axonal recordings revealed AP deficits only in young adult Scn1a+/– PV-INs, and low dose tetrodotoxin preferentially exacerbated AP changes in this group, supporting an age-dependent NaV1.1 related axonal dysfunction during early development.
In Paper II, I used interface chamber field recordings from slices of Scn1a+/– and forebrain specific Kir4.1 knockout mice. Both models showed reduced ripple frequencies in CA1 during SPW and elevating extracellular K+ further destabilized SPW-R synchronization, particularly in slices from Scn1a+/– mice.
Together, these studies indicate that NaV1.1 related axonal dysfunction in PV-INs and impaired astrocytic Kir4.1 mediated K+ buffering converge on disturbed hippocampal SPW-R dynamics, linking interneuron and glial channelopathies to seizure susceptibility and memory related network deficits.
Additional information
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