The principal research strategy in the Developmental Neurogenetics Laboratory is to apply mutational analysis to learn how genes regulate neuronal excitability and network synchronization within the mammalian central nervous system. Spontaneous and transgenic mutations that express neurological phenotypes in the mouse provide a valuable opportunity to identify excitability genes and examine their role in synaptic plasticity in the developing brain. Brain wave (EEG) phenotypes emerge from altered neuronal signaling properties, and are of special interest. Six mouse mutants causing spike-wave synchronization of the neocortex have been discovered in our laboratory, and four (tottering, lethargic, ducky, and stargazer) are linked to mutations of subunits of neuronal voltage-gated calcium ion channels. Study of these mice have led to the identification of novel members of the gene family, and a new understanding of how related molecules rescue function and determine selective vulnerability within thalamocortical pathways. Other new mouse models for human epilepsy syndromes involving mutant ion channel, receptor, and synaptic vesicle proteins are being analyzed to pinpoint the neural network and specific electrophysiological abnormalities characteristic of the human disorder. We also explore the presynaptic release process and activity-induced changes of downstream gene expression in epileptic brain to identify regulatory pathways that are critical mechanisms of disease progression.