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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Axonal dysfunctions in Dravet Syndrome

Alternative title: Aksonale dysfunksjoner i Dravet syndrom

Awarded: NOK 8.0 mill.

Dravet syndrome is a severe form of childhood epilepsy. During an initial period of normal development, infants suffering from Dravet syndrome develop epileptic seizures at about half a year of age, often in combination with fever (so called febrile seizures). During the first years of life, patients may develop a variety of epileptic seizures, which have a strong impact on their further development and they are often diagnosed with different forms of behavioral disorders including autism. Dravet syndrome was found to be associated with a genetic defect in one particular gene: About 70-80% of the patients show a mutation in the SCN1A gene, which contains the information to produce a specific type of sodium ion channel. Sodium ion channels are especially important for fast electrical signaling in the central nervous system. The discovery of the SCN1A mutation as a major determinant of Dravet syndrome identified it as a disease, a "channelopathy", and triggered a number of new research projects studying how mutations of ion channel-related genes may cause epilepsy and cognitive disorders. Together with international collaborators, we are interested in the mechanisms by which the SCN1A channelopathy changes complex brain signaling. Using our expertise on inhibitory neurons expressing the SCN1A gene, my project team studies how dysfunctions of sodium ion channels affects complex activity in neuronal networks. We use transgenic mice carrying a SCN1A deficit (Scn1a+/- mice), which efficiently mimic Dravet syndrome pathologies. The use of brains slices from mice gives us the opportunity to record signaling in single cells at high resolution and at the same time study their interaction with ongoing network activity. Understanding the effects of ion channel dysfunctions on complex neuronal activities is highly relevant for improving the treatment of patients and for our basic understanding of brain functions.

Dravet Syndrome (DS) is a severe form of childhood epilepsy with an early onset (under one year) affecting cognitive development and often causing sudden death. Most DS patients show a mutation in the SCN1A gene, which encodes for a sodium channel subunit (NaV1.1) highly expressed in axons of cortical GABAergic interneurons. These inhibitory neurons are responsible for balancing cortical brain activity by the release of the neurotransmitter GABA from their axonal terminals. Impairments of GABAergic inhibition are known to lead to epilepsy and other cognitive disorders. In close agreement, transgenic mice with reduced SCN1A gene expression (DS mice) reproduce key features of DS symptoms and show dysfunctions in parvalbumin-expressing GABAergic interneurons (PV-INs), as well as deficits in cortical network oscillations. These dysfunctions are believed to be caused by changes in action potential (AP) signalling in PV-IN axons. My project aims to identify how axonal functions are impaired in DS mice and to link the axonal deficits to dysfunctions in neuronal network oscillations. So far, other studies were unable to directly resolve the ion channel activity in PV-IN axons of DS mice because of the difficulties in accessing the fine axonal structures. My experience on measuring subcellular axonal functions as well as neuronal network oscillations provides the unique possibility to advance our understanding of the causal relationship between axonal currents, AP signalling and GABAergic inhibition in neuronal networks. This knowledge is important for understanding complex brain activities in general, but also to improve the treatment of neurological disorders such as DS.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol