Enhancing GluN2A-type NMDA receptors impairs long-term synaptic plasticity and learning and memory

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• N-methyl-D-aspartic acid receptors (NMDARs) are crucial for synaptic transmission and plasticity.
• Dysregulation of NMDARs is linked to cognitive deficits and intellectual disability.

Purpose of the Study:

• To investigate the functional impact of a rare NMDAR subunit GluN2A (K879R) variant found in an intellectual disability patient.
• To elucidate the molecular mechanism by which this variant affects receptor function and neuronal activity.

Main Methods:

• Identified a rare K879R variant in the GluN2A subunit of NMDARs.
• Utilized cell surface expression assays and electrophysiology in mouse hippocampal neurons.
• Generated and analyzed GluN2A K879R knock-in mouse models.

Main Results:

• The K879R mutation increases GluN2A-NMDAR surface expression by disrupting an endoplasmic reticulum retention signal.
• Enhanced GluN2A-NMDAR currents but suppressed GluN2B-NMDAR and AMPA receptor currents in CA1 neurons.
• GluN2A K879R knock-in mice exhibit impaired synaptic transmission, learning, memory, and long-term potentiation/depression (LTP/LTD).

Conclusions:

• Elevated synaptic GluN2A-NMDAR function due to the K879R variant impairs long-term synaptic plasticity.
• This impairment in plasticity underlies the observed learning and memory deficits, providing a molecular basis for intellectual disability.