GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

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Abstract
The cellular etiology of seizures in CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), remains elusive. Given that Cln2 R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical GABAergic interneuron populations, we hypothesized that these 2 events might be causally related. To study the cell-autonomous effects of interneuron-specific TPP1 deficiency, we first generated transgenic mice expressing loxP -flanked lysosomal membrane–tethered TPP1 (TPP1LAMP1 mice) on the Cln2 R207X/R207X genetic background, and then crossed TPP1LAMP1 mice with Vgat-Cre mice. These Vgat-Cre; TPP1LAMP1 mice accumulated storage material in cortical and striatal interneurons. Vgat-Cre; TPP1LAMP1 mice also died more readily after pentylenetetrazole-induced seizures, indicating that interneuron-specific TPP1 deficiency renders these mice more susceptible to seizure-induced mortality. We also selectively activated interneurons using designer receptors exclusively activated by designer drugs (DREADDs) in Vgat-Cre; Cln2 R207X/R207X mice. Electroencephalogram monitoring revealed that DREADD-mediated activation of interneurons markedly accelerated the onset of spontaneous seizures and seizure-associated death in Vgat-Cre; Cln2 R207X/R207X mice, suggesting that modulating interneuron activity can exacerbate epileptiform abnormalities. Taken together, these results provide mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.
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Funding Information
  • Noah’s Hope/Hope 4 Bridget (N/A)
  • Washington University in St Louis, McDonnell Center for Systems Neuroscience Small Grant Award (N/A)
  • Institutional support from the Department of Pediatrics, Washington University in St Louis (N/A)
  • NIH (P50 HD103525 to the Washington University Intellectual)
  • NIH (Developmental Disabilities Research Center)
  • National Institute of Neurological Disorders and Stroke (R01 NS100779)
  • National Institute of Neurological Disorders and Stroke (RM1 NS132962)

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