Rapid glutamatergic neurotransmission: NMDA and AMPA receptors as modulators of neuronal excitability and their implication in excitotoxicity

Abstract

Synaptic transmission is the fundamental process of neuronal communication through chemical and electrical signaling. In chemical synapses—the most abundant type in the CNS—the arrival of an action potential depolarizes the presynaptic terminal and opens voltage-gated Ca²⁺ channels. The subsequent rise in intracellular Ca²⁺ activates the SNARE complex (synaptobrevin, syntaxin, SNAP-25), triggering the exocytosis of synaptic vesicles that release neurotransmitters such as glutamate.Glutamate, the main excitatory neurotransmitter, acts on ionotropic receptors (NMDA, AMPA, kainate) and metabotropic receptors (mGluR1–8). AMPA receptors mediate fast responses through Na⁺ influx, whereas NMDA receptors require prior depolarization to remove the Mg²⁺ block and allow Ca²⁺ entry, functioning as coincidence detectors. Coordinated activation of NMDA and AMPA receptors is essential for synaptic plasticity, the molecular basis of learning.During long-term potentiation (LTP), Ca²⁺ influx through NMDA receptors activates CaMKII and PKC, promoting the insertion of additional AMPA receptors and strengthening synaptic transmission. Conversely, long-term depression (LTD) involves a reduction of AMPA receptors, modulating synaptic efficacy. Together, these processes enable functional adaptation of neural circuits.The same glutamatergic pathway that supports plasticity can also induce neuronal injury when excessively activated. Excitotoxicity results from overstimulation of NMDA receptors and excessive Ca²⁺ influx, which activates proteases, oxidative stress pathways, mitochondrial dysfunction, and ultimately leads to neuronal death. This mechanism is implicated in neurodegenerative disorders such as Alzheimer’s disease, ALS, Huntington’s disease, epilepsy, and ischemic brain injury.The balance between vesicular glutamate transport (vGLUT), glutamate reuptake (EAAT1–5), receptor regulation, and Ca²⁺ homeostasis determines whether glutamatergic signaling remains physiological or becomes harmful. Disruption of these systems causes extracellular glutamate accumulation and sustained neurotoxicity. Understanding these mechanisms is essential for developing neuroprotective therapies aimed at modulating NMDA receptors, reducing oxidative stress, or enhancing glutamate clearance.