Which neurotransmitter and receptor system is primarily involved in excitotoxicity and synaptic plasticity?

• A. GABA activating GABA-B receptors
• B. Acetylcholine acting on nicotinic receptors
• C. Glutamate activating NMDA receptors (and AMPA) leading to Ca2+ influx
• D. Dopamine acting on D1 receptors

Answer: (C)

Glutamatergic signaling, especially through NMDA receptors, is central to both excitotoxicity and synaptic plasticity. Glutamate is the main fast excitatory neurotransmitter in the CNS, and NMDA receptors are unique because they allow calcium to enter the neuron when activated and the membrane is depolarized (the Mg2+ block is relieved). In normal activity, calcium influx through NMDA receptors triggers intracellular signaling cascades (like CaMKII and CREB) and receptor trafficking that strengthen synapses, supporting long-term potentiation and plastic changes. But when glutamate is released in excess or uptake is impaired, overactivation of NMDA receptors (and to some extent AMPA receptors) causes a large calcium influx that activates degradative enzymes, disrupts mitochondria, and leads to neuronal injury or death—excitotoxicity. The other listed systems modulate excitability or plasticity in different contexts—GABA receptors provide inhibition, acetylcholine on nicotinic receptors is a different excitatory pathway, and dopamine on D1 receptors influences plasticity in specific circuits but does not directly drive the primary excitotoxicity/plasticity mechanism via calcium signaling through NMDA receptors. Thus, the glutamate-NMDA (and AMPA) receptor system best explains both processes.