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Inhibitory Synapse Formation in a Co-culture Model Incorporating GABAergic Medium Spiny Neurons and HEK293 Cells Stably Expressing GABAA Receptors
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GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation

Jia Tong1,2, Jingjing Gao2,3, Yawei Qi2

  • 1The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, He'nan, China.

Translational Psychiatry
|December 18, 2024
PubMed

Insights

Palmitoyl protein thioesterase 1 (PPT1) depalmitoylates GABAAR, a key inhibitory neurotransmission protein. PPT1 mutations impair learning and memory, revealing a new molecular pathway in CLN1 disease.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Infantile neuronal ceroid lipofuscinosis (CLN1 disease) is a fatal neurodegenerative disorder.
  • Mutations in the CLN1 gene, encoding palmitoyl protein thioesterase 1 (PPT1), cause CLN1 disease.
  • Identifying PPT1 substrates is crucial for understanding CLN1 disease pathogenesis.

Purpose of the Study:

  • To identify depalmitoylation substrates of PPT1.
  • To investigate the role of PPT1 in regulating GABAAR palmitoylation.
  • To elucidate the molecular mechanisms underlying CLN1 disease.

Main Methods:

  • Biochemical assays to identify PPT1 substrates.
  • Analysis of GABAAR α1 subunit palmitoylation.
  • Electrophysiological recordings in mouse models.
  • Behavioral tests for learning and memory.

Main Results:

  • GABAAR was identified as a substrate of PPT1.
  • PPT1 depalmitoylates the GABAAR α1 subunit at Cys-260 and binds to Cys-165 and -179.
  • PPT1 deficiency or mutations impaired learning and memory in mice.
  • Disrupted synaptic transmission and oscillations were observed in the CA1 region.

Conclusions:

  • PPT1 plays a critical role in maintaining GABAAR palmitoylation homeostasis.
  • PPT1 mutations disrupt inhibitory neurotransmission and cognitive function.
  • A novel molecular pathway involving PPT1 and GABAAR in CLN1 disease has been revealed.

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