To understand neural computation and the dynamics in the brain, we usually focus on the connectivity among neurons. In contrast, the properties of single neurons are often thought to be negligible, at least as far as the activity of networks is concerned. In this talk, I will contradict this notion and demonstrate how the biophysics of action-potential generation can have a decisive impact on network behaviour. Our recent theoretical work shows that, among regularly firing neurons, the somewhat unattended homoclinic type (characterized by a spike onset via a saddle homoclinic orbit bifurcation) particularly stands out: First, spikes of this type foster specific network states - synchronization in inhibitory and splayed-out/frustrated states in excitatory networks. Second, homoclinic spikes can easily be induced by changes in a variety of physiological parameters (like temperature, extracellular potassium, or dendritic morphology). As a consequence, such parameter changes can even induce switches in network states, solely based on a modification of cellular voltage dynamics. I will provide first experimental evidence and discuss functional consequences of homoclinic spikes for the design of efficient pattern-generating motor circuits in insects as well as for mammalian pathologies like febrile seizures. Our analysis predicts an interesting role for homoclinic action potentials as an integral part of brain dynamics in both health and disease.

The origins, mechanisms and consequences of epilepsy in the developing brain are incompletely understood. Many developmental epilepsies have a genetic basis and their mechanisms stem from deficits in the function of one or numerous genes. Others, such as those that follow prolonged febrile seizures or severe birth asphyxia in a ‘normal’ brain may depend on the interaction of the insult with the rapidly evolving brain cells and circuits. Yet, how early-life insults may provoke epilepsy is unclear, and requires multiple levels of analysis: behavior, circuits, cells [neurons, glia] and molecules. Here we discuss developmental epileptogenesis, addressing some of its special features: the epilepsy phenotype, the effects insults on the maturation of brain circuits, the role of neuron-glia-neuron communication in cellular and circuit refinement, and how transient epileptogenic insults provoke enduring changes in the structure, connectivity and function of salient neuronal populations. We will highlight resolved questions- and the many unresolved issues that require tackling in 2022 and beyond.

Genetic mutations of the SCN1A gene, the voltage gated sodium channel NaV1.1, cause well-defined epilepsies, including the severe developmental and epileptic encephalopathy Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+), as well as a severe form of migraine with aura, familial hemiplegic migraine (FHM). More recently, they have been identified in an extremely severe early infantile encephalopathy. Functional studies and animal models have contributed to disclose pathological mechanisms, which can be often linked to a straightforward loss- vs gain- of channel function. However, although this simple dichotomy is pertinent and useful, detailed pathological mechanisms in neuronal circuits can be more complex, sometimes because of unexpected homeostatic or pathologic responses. I will compare pathological mechanisms of epilepsy and migraine mutations studied with cellular, animal and computational models, highlighting a novel homeostatic response implemented by CCK-positive GABAergic neurons in a mouse model of Dravet syndrome, which may be boosted in therapeutic approaches.