Gain of Function of NMDA Receptors and Increased Risk of Epilepsy/Seizures
Gain of function of NMDA receptors is associated with increased risk of epilepsy or seizures in a neural circuit due to enhanced excitatory neurotransmission, reduced magnesium block, and prolonged synaptic currents.
Mechanisms of NMDA Receptor Gain of Function in Epileptogenesis
- NMDA receptor gain of function mutations (such as GluN2AN615K, GluN2BN615I, and GluN2BV618G) abolish voltage-dependent magnesium block, allowing excessive calcium influx and neuronal hyperexcitability 1
- These mutations enhance the magnitude of excitatory postsynaptic currents (EPSCs), directly contributing to epilepsy phenotypes 1
- Gain of function mutations in GRIN2B (encoding GluN2B subunit of NMDA receptors) have been linked to epileptic encephalopathies, including infantile spasms 2
- During status epilepticus, there is increased surface expression of NR1 subunits of NMDA receptors, leading to an increase in number of functional NMDA receptors on neurons 3
Comparison with Na+ Channel Gain of Function
- While Na+ channel gain of function also contributes to seizures, NMDA receptor hyperactivity has distinct pathophysiological consequences:
- NMDA receptors mediate slow, prolonged excitatory currents compared to the fast, transient currents of Na+ channels 1, 4
- NMDA receptors allow calcium influx, triggering intracellular signaling cascades that promote long-term neuronal hyperexcitability 1
- NMDA receptor gain of function mutations specifically disrupt magnesium block, creating a unique mechanism of hyperexcitability 2
Clinical Implications and Evidence
- Epilepsy affects over 70 million people worldwide, with significant impact on quality of life and increased mortality risk 5
- Seizures represent an extremely heterogeneous group of medical conditions ranging from benign cases to life-threatening situations such as status epilepticus 6
- Approximately 10% of the population will experience at least one seizure during their lifetime 7
- Focal seizures, which can arise from localized hyperexcitability, account for most epilepsy cases in both children and adults 4
Therapeutic Considerations
- NMDA receptor antagonists may have therapeutic potential for epilepsy associated with NMDA receptor gain of function 2
- GluN2B-selective inhibitors like radiprodil retain their pharmacological profile in the presence of gain of function mutations, suggesting potential therapeutic value 2
- Anti-epileptic drugs that modulate other ion channels may be less effective in cases where NMDA receptor hyperactivity is the primary mechanism 1, 2
Common Pitfalls in Understanding Neural Hyperexcitability
- Failing to distinguish between different mechanisms of neural hyperexcitability can lead to suboptimal treatment choices 1, 2
- Not recognizing that gain of function in inhibitory channels (such as Cl- channels or M-current) would typically reduce seizure risk, not increase it 5
- Overlooking the role of calcium signaling in NMDA receptor-mediated epileptogenesis, which extends beyond simple membrane depolarization 1
In conclusion, while both NMDA receptor and Na+ channel gain of function can contribute to seizures, the NMDA receptor mechanism involves unique features including calcium signaling, prolonged excitatory currents, and disrupted magnesium block that make it particularly epileptogenic in neural circuits.