Neuron-derived neurotrophic factor-positive interneurons: a cellular target for anti-seizure therapies

Background Failure of epilepsy pharmacotherapy is common, justifying efforts to identify optimal cell targets for advanced therapies. Genetic manipulations of the inhibitory system in principle offer a finely tuned intervention that cannot be achieved with a broad reduction of pyramidal neuron excitability. In this context, neuron-derived neurotrophic factor-expressing (NDNF+) interneurons evoke long-lasting GABA A and GABA B receptor-mediated inhibition. However, their contribution to restraining hyperexcitability during epileptiform activity remains unexplored. Methods To address this, we employed calcium imaging, optogenetics, and chemogenetics in an NDNF-Cre mouse line to investigate how NDNF+ interneurons influence cortical and hippocampal hyperactivity and spontaneous seizures. Findings We show that NDNF+ interneurons are actively recruited during interictal spikes and focal seizures, although more slowly than parvalbumin-positive interneurons (mean difference: 2.8 s, p=0.023). Optogenetic hyperpolarisation of NDNF+ interneurons exacerbates epileptic discharges (normalised seizure-duration mean difference: 0.23, p=0.0474), whereas their depolarisation suppresses focal seizures, even when the optogenetic stimulus is delayed by several seconds from seizure onset (normalized seizure-duration mean difference: −0.27, p=0.03). This effect is largely mediated by GABA B receptors. Additionally, chemogenetic depolarisation of NDNF+ interneurons has an important anti-seizure effect in the hippocampus both ex vivo (normalised seizure-duration mean difference: −0.92, p < 0.001) and in vivo . Interpretation Collectively, these findings establish NDNF+ neurons as key regulators of both cortical and hippocampal excitability even during epileptic activity, and identify them as promising cellular targets for the development of anti-seizure therapies. Funding Epilepsy Research UK, Wellcome, the Medical Research Council, the Gatsby Charitable Foundation, and The Rosetrees Trust.