Δ9-tetrahydrocannabinol modulates the proteasome system in the brain

Area of Science:

• Neuroscience
• Proteomics
• Pharmacology

Background:

• Cannabis, containing Δ⁹-tetrahydrocannabinol (THC), is a widely used illicit drug.
• THC modulates cannabinoid type-1 (CB1) receptors, impacting brain functions like cognition.
• CB1 receptors are crucial in presynaptic terminals, regulating neurotransmitter release.

Purpose of the Study:

• To identify synaptic proteins and pathways affected by a single dose of THC.
• To investigate the impact of THC on proteasome function in the hippocampus.
• To explore potential mechanisms underlying THC-induced cognitive impairment.

Main Methods:

• Proteomic screening of hippocampal synaptosomal fractions 3 hours after THC administration.
• Isobaric labeling approach to identify and quantify proteins.
• Gene set enrichment analysis and network topology-based scoring to identify key pathways and proteins.

Main Results:

• Identified 2040 synaptic proteins, with 122 significantly altered by THC.
• Observed over-representation of mitochondrial and metabolic functions.
• Pinpointed significant alterations in proteasome system (PS) proteins and decreased 20S proteasome activity.

Conclusions:

• THC administration modulates hippocampal synaptic proteome, particularly affecting proteasome function.
• Impaired proteasome activity may contribute to aberrant synaptic plasticity and cognitive deficits.
• This study provides novel insights into the molecular mechanisms of THC's effects on the brain.