Mechanisms underlying continuous spike-waves during slow-wave sleep in a mouse model of focal cortical dysplasia

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 DESCRIPTION (provided by applicant): The long-term goal of this research project is to gain an understanding of the broader relationship between sleep, long-range sensorimotor circuits, and epilepsy circuits associated with a mouse model of focal cortical dysplasia (FCD). FCD and related malformations of cortical development (MCDs) are highly correlated with childhood seizure syndromes and cognitive disabilities. MCDs represent an increasingly recognized cause of medically intractable epilepsy. The development of more effective therapies will benefit from a deeper understanding of the pathophysiology and mechanisms of epileptogenesis in animal models. We will study long-range sensorimotor circuit properties in a unilateral single focal neonatal freeze lesion in S1 (SFFLS1R) treated mice. In Aim 1, we will obtain 24-hour EEG data from SFFLS1R mice to validate our preliminary finding that these animals developed continuous spike-waves during slow-wave sleep (CSWS) epileptiform discharges. CSWS is a human epileptic syndrome that is associated with the EEG pattern of electrical status epilepticus during slow wave sleep (ESES). We will then examine the idea that during the pre-ictal state (i.e. latent period), abnormal pre-ictal discharges (APDs) precede CSWS activity and are a biomarker for the severity of CSWS seizures in the same animals. In Aim 2, we will examine the hypothesis that large scale reorganization of long-range sensorimotor and corticothalamic circuits, in addition to local circuits, is required to support generalized APDs and CSWS in SFFLS1R animals. We will combine mouse genetics and the ChR2-assistant circuit mapping (CRACM) approach to characterize the maladaptive reorganization of long- range vs. local inhibitory cortical circuits in the malformed S1. In Aim 3, we will further use complementary approaches to test the idea that paroxysmal epileptiform discharges in SFFLS1R mice are mediated by long- range circuits acting on their targets in the malformed S1 in vivo. We will first use opto- and chemo-genetics tools to manipulate circuit components in vivo to demonstrate whether and to what extent CSWS seizures are modulated by activation/inactivation of certain circuit components. We will then take advantage of the modified enriched environment to determine whether and to what extent CSWS seizures are modulated by sensory experiences during the latent period. Upon successful completion of this project, we can associate chronic spontaneous CSWS/ESES seizures with FCD in a mouse model. Upon successful completion of this project, we can link dynamic changes of long-range circuits with ictogenesis, which will guide our understanding of why dynamic bistability exists in thalamocortical circuits in the pathological state. Understanding the mechanisms by which normal sleeping and sensorimotor circuits are transformed into epileptic circuits will help develop circuit-based treatment strategies for intractable epilepsy associated with CSWS/ESES and FCDs/MCDs. The chronic FCD animal model can potentially be used to develop behavior- based therapies and screen drug targets for novel therapies related to ESES, MCD epilepsy.