. Synaptic integration and plasticity are the cellular mechanisms of information pro- cessing, learning, and memory. How these fundamental processes are disrupted in epilepsy is not understood. Generalized Epilepsy with Febrile Seizures Plus/Dravet syndrome (GEFS+/DS) is a spectrum of epilepsy disor- ders linked to mutations of the SCN1B gene which cause seizures, neurodevelopmental delays, and early death. To develop treatments for seizures/cognitive deficits of GEFS+/DS epilepsies, there is a critical need to identify mechanisms by which SCN1B mutations disrupt cellular-level information processing and learning. Our long- term goal is to define general principles linking genes to disrupted synaptic integration and plasticity in such neurodevelopmental disorders. The overall objective of our proposal is to define how the interplay between syn- apses, dendritic physiology, and somatic physiology impair synaptic integration and plasticity in the Scn1b knock- out (KO) mouse model of GEFS+/DS. Our central hypothesis is loss of Scn1b dysregulates ion channels and dendrite excitability, disturbing integration and plasticity. To test this hypothesis, we will complete three Aims:
Aim 1 : Determine the mechanisms of somatic and dendritic hyperexcitability in Scn1b KO neurons. Based on preliminary data, our hypothesis is that both dendrites and somata of Scn1b KO CA1 pyramidal neu- rons exhibit intrinsic hyperexcitability in part due to abnormal HCN channel activity. We will test this hypothesis with whole cell somatic and dendritic recordings, immunohistochemistry, and cell morphology analyses.
Aim 2 : Determine the mechanisms of altered synaptic integration in Scn1b KO neurons. Based on our preliminary data, our hypothesis is that loss of Scn1b fundamentally alters the translation of inputs into outputs, with both temporal and spatial synaptic integration abnormally enhanced due to dendritic hyperexcitability and disrupted synaptic physiology. We will use whole cell recordings to test how temporal and spatial features of input/output functions are altered in Scn1b KO neurons in response to naturalistic patterns of synaptic inputs.
Aim 3 : Test the hypothesis that Scn1b disruption alters synaptic learning rules and gating by GABA that dictate plasticity. Based on our preliminary data, our hypothesis is that synaptic learning rules governing LTP and LTD induction are re-shaped due to interplay between suppressed excitation, hyperexcitable intrinsic properties, and abnormal gating by aberrant depolarizing inhibition after loss of Scn1b. We will test how input patterns that evoke LTP and LTD shift after loss of Scn1b, and how inhibition influences this plasticity. Upon successful completion of the proposed research, we will have defined detailed mechanisms by which changes in neuron intrinsic and synaptic physiology and their interactions re-shape the cellular forms of neural processing and learning in the Scn1b KO mouse model of GEFS+/DS. This contribution will provide mechanistic links between genetic changes, primary neurophysiology phenotypes, and neuronal processing deficits underly- ing seizures and the learning, memory, and cognition impairments in GEFS+/DS epilepsies.
The proposed research is relevant to public health because it seeks to understand how genetic mutations cause brain cell hyperexcitability and change the way these cells process information and learn, leading to seizures, developmental delays, and cognitive impairments. Our research will define how deficits in neuron excitability and synaptic communication interact to alter plasticity in a transgenic mouse model of Generalized Epilepsy with Febrile Seizures Plus and Dravet syndrome, severe childhood epilepsy disorders. Our work aligns with the mission of the NINDS because we seek to uncover causes of neurodevelopmental disease, discover avenues for therapy development, and ease the burden of this disorder on patients, their families, and society.
