Hippocampal integration during epileptogenesis of genetic epilepsies: Developmental intervention

• Applicants: Professor Dr. Heinz Beck; Tony Kelly, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 377782854

Over the last 20 years there has been a dramatic increase in the number of epilepsies causally linked to genetic mutations. Many of the mutated genes code for ion channels and the mutations are responsible for a loss or gain of channel function (LOF or GOF). In acquired epilepsies we know that aberrant expression of specific ion channels during the period of epileptogenesis results in not only changes in intrinsic properties but changes in the integration of inputs. In turn, this results in the altered recruitment of local networks. However, as yet, little is known regarding how mutations underlying genetic epilepsies alter pathway-specific dendritic integration, and consequently the recruitment of micro-networks. Furthermore, it is unknown how and when during development these changes manifest.A recently discovered GOF mutation in SCN2A causing a severe neonatal onset epilepsy was characterized and a Scn2aA263V knock-in (KI) mouse model developed by members of projects P5 and P71,2. Preliminary data from P7 has examined the spatiotemporal evolution of seizure activity in this model in intact mice. Multisite silicon probe recordings suggest that during development seizure activity is initially limited to the hippocampal network during the first 2 weeks of life. Stereotypical ictal activity in the hippocampus begins with 2-5 seconds of gamma activity in CA3 which about 20-30 s later is followed by bilateral seizure activity in CA1. These results point towards the CA3 region as key early generator of abnormal activity. However, it is unknown which precise circuit changes take place in the CA3 region, how the abnormal CA3 output is processed by CA1, and how it is converted into hippocampal output. We will use the Scn2aA263V mouse model to examine during epileptogenesis (i) dendritic information processing at the different input zones on CA1 and CA3 pyramidal neurons, (ii) the properties of canonical inhibitory micro-networks that control excitability of the CA1 and CA3 pyramidal neurons, and (iii) the contribution of altered pathway integration to network activity and hippocampal function in awake behaving animals. In addition, we will screen the effect of other mutations on the local micro-network recruitment in additional mouse models generated by the consortium. This project will lead to an understanding of the circuit and cellular mechanisms underlying seizure activity in a genetic epilepsy model, and provides a template for the study of circuit abnormalities in additional genetic models.

• DFG Programme: Research Units
• Subproject of: FOR 2715: Epileptogenesis of genetic epilepsies