A 45-year-old man comes to the office for follow-up. He was diagnosed with focal epilepsy 2 years ago and has been treated with several antiepileptic medications. Over the last 6 months, his seizure frequency has increased despite compliance with medical therapy. Neurologic examination and brain imaging are unremarkable. The patient is started on a new antiepileptic medication that selectively blocks voltage-gated calcium channels. This medication most likely affects which of the following steps of neurotransmission?
Neurons communicate with each other via synapses, regions where the axon terminal of a presynaptic neuron transmits chemical signals to the dendrites of a postsynaptic neuron. Binding of an excitatory neurotransmitter (eg, glutamate) to a postsynaptic neuron causes opening of ligand-gated sodium channels, leading to sodium influx and membrane depolarization. This depolarization impulse is transmitted from the dendrites through the cell body to the axon hillock, which contains a large number of voltage-gated sodium channels. Once the axon hillock becomes sufficiently depolarized, an action potential is triggered and propagates along the axon via a steady influx of sodium ions. When the action potential reaches the axon terminal, voltage-gated calcium channels open and allow the influx of calcium, which is essential for the fusion and release of neurotransmitter vesicles into the synaptic cleft.
Seizures occur due to abnormal, synchronized firing of hyperexcitable neurons in the brain, and many antiepileptic medications work by modifying electrochemical transmission between neurons. Gabapentin is an anticonvulsant that works by inhibiting presynaptic voltage-gated calcium channels, whereas levetiracetam acts downstream by disrupting vesicle fusion.
(Choice A) Antiepileptic medications such as phenytoin and carbamazepine disrupt the generation and propagation of action potentials (in the axon hillock and axon proper, respectively) by blocking voltage-gated sodium channels.
(Choices B and D) Neurotransmitters are synthesized in the presynaptic neuronal cell body and transported to the axon terminal (via kinesin motor proteins), where they are packaged in synaptic vesicles and primed for release.
(Choice E) Although the endoplasmic reticulum contains calcium release channels, these do not directly participate in neurotransmission. Release of calcium from the endoplasmic reticulum is more important for skeletal muscle contraction.
Educational objective:
Voltage-gated sodium channels are important for the generation and propagation of action potentials. When the action potential reaches the axon terminal, voltage-gated calcium channels open and allow the influx of calcium, which is essential for the fusion and release of neurotransmitter vesicles into the synaptic cleft.