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

TL;DR

PPT1 deficiency in mice causes dysfunction in brain cells that control neural rhythms, leading to seizures and brain damage.

Contribution

This study reveals that PPT1 deficiency causes early dysfunction in GABAergic interneurons, leading to seizures and neurodegeneration in CLN1 disease.

Findings

PPT1 deficiency activates caspase 3 in PV+ interneurons and disrupts theta-gamma coupling in early disease stages.

Late-stage PPT1 deficiency causes neuronal loss, spontaneous seizures, and pathological ripples.

Diazepam treatment partially restores oscillatory coupling and reduces seizure-like activity.

Abstract

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.

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