Developmental Epileptic
developmental epileptic encephalopathy
Investigating activity-dependent processes in cerebral cortex development and disease
The cerebral cortex contains an extraordinary diversity of excitatory projection neuron (PN) and inhibitory interneurons (IN), wired together to form complex circuits. Spatiotemporally coordinated execution of intrinsic molecular programs by PNs and INs and activity-dependent processes, contribute to cortical development and cortical microcircuits formation. Alterations of these delicate processes have often been associated to neurological/neurodevelopmental disorders. However, despite the groundbreaking discovery that spontaneous activity in the embryonic brain can shape regional identities of distinct cortical territories, it is still unclear whether this early activity contributes to define subtype-specific neuronal fate as well as circuit assembly. In this study, we combined in utero genetic perturbations via CRISPR/Cas9 system and pharmacological inhibition of selected ion channels with RNA-sequencing and live imaging technologies to identify the activity-regulated processes controlling the development of different cortical PN classes, their wiring and the acquisition of subtype specific features. Moreover, we generated human induced pluripotent stem cells (iPSCs) form patients affected by a severe, rare and untreatable form of developmental epileptic encephalopathy. By differentiating cortical organoids form patient-derived iPSCs we create human models of early electrical alterations for studying molecular, structural and functional consequences of the genetic mutations during cortical development. Our ultimate goal is to define the activity-conditioned processes that physiologically occur during the development of cortical circuits, to identify novel therapeutical paths to address the pathological consequences of neonatal epilepsies.
Mechanistic insights from a mouse model of HCN1 developmental epileptic encephalopathy
Pathogenic variants in HCN1 are associated with severe developmental and epileptic encephalopathies (DEE). We have engineered the Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse which is a homolog of the de novo HCN1 M305L recurrent pathogenic variant. The mouse recapitulates the phenotypic features of patients including having spontaneous seizures and a learning deficit. In this talk I will present experimental work that probes the molecular and cellular mechanisms underlying hyper-excitability in the mouse model. This will include testing the efficacy of currently available antiepileptic drugs and a novel precision medicine approach. I will also briefly touch on how disease biology can give insights into the biophysical properties of HCN channels.