The proper functioning of neuronal circuits critically depends on the establishment of balanced of excitation and inhibition during development. We hypothesize that failure of this maturational process can lead to epileptic disorders such as Infantile Spasms syndrome (IS or West syndrome), a group of devastating childhood epileptic encephalopathies. Specifically, we hypothesize that activity deprivation during a key developmental window triggers abnormal recruitment of homeostatic plasticity mechanisms, which results in an acquired imbalance between cortical excitation and inhibition. We propose that alterations in the structural maturation of excitatory and inhibitory synapses are likely to contribute to the circuit changes that underlie IS epileptic encephalopathies. Therefore, in this proposal we aim to use a combination of electrophysiological and structural methods to study the development of connectivity between excitatory and inhibitory interneurons in an in vitro model of IS. We expect this will provide insights into how excitatory and inhibitory neurons act to homeostatically regulate network activity during normal development and also how their dysfunction might contribute to network excitability disorders.
The proper functioning of neuronal circuits critically depends on the establishment of balanced excitation and inhibition during development. We know that activity blockade during a key developmental window interferes with the maturation of excitatory and inhibitory circuits and brings post-deprivation seizures. Identifying what are the cortical circuit elements that contribute to the establishment of this aberrantly hyperactive circuit is a key step towards developing targeted therapeutic strategies for Infantile Spasm epilepsy. DESCRIPTION (provided by applicant): The proper functioning of neuronal circuits critically depends on the establishment of balanced of excitation and inhibition during development. We hypothesize that failure of this maturational process can lead to epileptic disorders such as Infantile Spasms syndrome (IS or West syndrome), a group of devastating childhood epileptic encephalopathies. Specifically, we hypothesize that activity deprivation during a key developmental window triggers abnormal recruitment of homeostatic plasticity mechanisms, which results in an acquired imbalance between cortical excitation and inhibition. We propose that alterations in the structural maturation of excitatory and inhibitory synapses are likely to contribute to the circuit changes that underlie IS epileptic encephalopathies. Therefore, in this proposal we aim to use a combination of electrophysiological and structural methods to study the development of connectivity between excitatory and inhibitory interneurons in an in vitro model of IS. We expect this will provide insights into how excitatory and inhibitory neurons act to homeostatically regulate network activity during normal development and also how their dysfunction might contribute to network excitability disorders.
