The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Ubiquitin-specific protease (USP) 6 is linked to intellectual disability and autism spectrum disorder.
• Previous research suggests USP6's role in higher brain function, but its direct impact on cognition remains unexplored.

Purpose of the Study:

• To investigate the role of USP6 in learning, memory, and synaptic plasticity.
• To elucidate the molecular mechanisms by which USP6 influences neuronal function and cognition.

Main Methods:

• Utilized transgenic mouse models with neuron-specific USP6 expression.
• Performed proteomic analysis of USP6 transgenic mouse cortex.
• Investigated N-methyl-D-aspartate receptor (NMDAR) function and ubiquitination.
• Examined USP6's effect on human embryonic stem cell-derived neurons.

Main Results:

• USP6 is highly expressed in human neurons and enhances learning and memory in mice.
• USP6 regulates NMDAR-dependent long-term potentiation and depression.
• USP6 overexpression reduces NMDAR ubiquitination, increasing its expression, stability, and cell surface presence.
• USP6 down-regulation impairs NMDAR distribution and synaptic function in human neurons.

Conclusions:

• USP6 enhances synaptic function and cognitive processes by stabilizing NMDARs.
• USP6 plays a critical role in modulating synaptic plasticity and neuronal communication.
• Targeting USP6 may offer therapeutic potential for cognitive disorders.