A researcher is exploring various methods to decrease neuronal loss after ischemic injury. During an experiment, the researcher induces focal cerebral ischemia in rodents; after a short time, there is ATP depletion and subsequent ionic derangements in cells within the infarction core. Increased release and impaired clearance of extracellular neurotransmitters is also noted. One particular neurotransmitter leads to sustained calcium influx in exposed neurons, initiating a toxic cascade that result in rapid cell death. Blockade of a receptor for which of the following neurotransmitters is most likely to decrease this type of neuronal injury?
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Ischemic neuron death (eg, stroke) typically extends beyond the borders of the primary infarction zone. Glutamate-induced excitotoxicity has emerged as a key player in the outward propagation of injury. The main events in this process are as follows:
Ischemic glutamate release: Within minutes of focal cerebral ischemia, neurons depolarize because of ATP depletion. Neuronal depolarization causes exocytosis of glutamate-containing vesicles. Clearance of glutamate is also impaired due to astrocyte dysfunction. The result is a sudden, massive surge of glutamate into the extracellular space.
NMDA receptor activation: Glutamate enters the synaptic cleft. The glutamate NMDA receptor is activated, increasing the conductance of cations and causing depolarization (and additional glutamate release) from neurons adjacent to the infarct core.
Intracellular calcium overload: Opening of the NMDA receptors causes calcium influx into the cell. Fluctuations of cytoplasmic calcium are normally buffered by the mitochondria and endoplasmic reticulum. Rapid calcium overload overwhelms the cell, causing mitochondrial dysfunction, free radical formation, and calcium-dependent protease activation.
Neuron death: The neuron suffers energetic failure (mitochondrial dysfunction) and macromolecule damage (eg, membrane lipid peroxidation, DNA cleavage). The neuron ultimately dies, ruptures, and releases more glutamate.
This vicious cycle of depolarization (excitotoxicity) and glutamate release has been identified as a final common pathway of brain tissue loss (eg, ischemic stroke, traumatic brain injury, Alzheimer dementia). NMDA receptor antagonists (eg, memantine) have neuroprotective effects for some patients with neurodegenerative diseases.
(Choices A and D) Dopamine and norepinephrine can increase neuronal calcium levels by activating calcium release from intracellular stores through the inositol triphosphate, second-messenger pathway. This homeostatic process promotes neuron growth and survival rather than cytotoxicity. Because these metabotropic (ie, G-protein coupled) receptors do not activate calcium channels in the plasma membrane, they do not depolarize the neuron on binding.
(Choice C) Glycine is an inhibitory neurotransmitter found primarily in the spinal cord rather than the brain. It acts on a ligand-gated ion channel that permits passage of chloride anions, causing hyperpolarization rather than excitation.
(Choice E) The 5-HT3 serotonin receptor is the only isoform that acts as a ligand-gated cation channel causing depolarization; however, this is mediated primarily by sodium and potassium, rather than calcium, influx. Furthermore, all other serotonin receptors are G-protein coupled, acting through second messengers (cyclic AMP).
Educational objective:
Glutamate is released from injured neurons, causing pathologic hyperactivation of NMDA receptors and leading to depolarization, calcium overload, and death of neighboring cells. This cascade of excitotoxicity contributes to neurodegeneration and propagation of neuron death after focal injury.