Dysfunction of GABAergic interneurons underlies altered neural network oscillations associated with epileptiform activity in PPT1-deficient mice.

The neuronal ceroid lipofuscinosis family of lysosomal storage diseases, also called CLN1 disease, is characterized by the deficiency of palmitoyl-protein thioesterase 1 (PPT1). In this study, we investigated the impact of PPT1 deficiency on hippocampal GABAergic interneurons (INs) and associated neural network oscillations in a PPT1-KI (CLN1 c.451 C > T (p.R151X)) mouse model. Using a combination of in vivo electrophysiology, immunostaining, and fiber photometry, we observed that PPT1 deficiency led to the activation of caspase 3 in parvalbumin-positive (PV+) INs, an increased activity of pyramidal neurons and theta/gamma oscillation power, and the disruption of theta-gamma cross-frequency coupling (CFC) in the early stage of the CLN1 disease model. In the late stage of the CLN1 disease model, we observed the reduced neuronal activity, extensive neuronal loss including PV+ INs, and the emergence of spontaneous epileptiform discharges and the pathological ripples. Treatment with diazepam partially restored oscillatory coupling and reduced seizure-like activities. Our research indicated that PPT1 deficiency leads to early selective impairment of PV+ INs, triggering overactivation of pyramidal neurons and network dysfunction, which consequently results in seizures and neurodegeneration. This research provides novel insights into the pathogenesis of CLN1 disease and potential therapeutic strategies for the intervention of CLN1 disease by improving the function of inhibitory INs via caspase inhibition.