Lysosomal TRPML1 activation modulates synaptic transmission and intrinsic neuronal excitability.

Abstract

The calcium channel TRPML1 regulates key functions in lysosomes and has emerged as a promising therapeutic target for lysosomal storage diseases and neurodegenerative diseases. While pharmacologically, TRPML1 activation has been shown to reduce storage burden, its impact on synaptic function and network activity is unknown. In this study, we examined how modulation of TRPML1 activity with agonist and antagonist affects synaptic transmission in mice of both sexes. In addition, we evaluated its therapeutic potential in a disease model of juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), a well-known lysosomal storage disorder. We report that activation of TRPML1 via bath application of ML-SA5 enhances excitatory synaptic transmission via a presynaptic mechanism and modulates intrinsic neuronal excitability of hippocampal neurons. In contrast, inhibiting TRPML1 has a postsynaptic effect, as the mEPSC amplitude is reduced in the presence of ML-SI1. Further, treatment with ML-SA5 partially rescued synaptic abnormalities in the disease model of JNCL, suggesting potential therapeutic benefits. These findings highlight the role of TRPML1 in regulating synaptic and intrinsic neuronal properties and its potential in the therapy of JNCL.