Question

A new drug called Xaelenfal is on the market. Xaelenfal is an AMPA receptor antagonist, meaning that it binds onto AMPA receptors without activating them and prevents glutamate from binding.

i. If I take the drug Xaelenfal, how will this effect EPSPs recorded in the postsynaptic neuron when an excitatory presynaptic neuron fires an action potential? (1 point)

ii. How will the drug Xaelenfal effect IPSPs in the postsynaptic neuron when an inhibitory presynaptic neuron fires an action potential? (1 point)

iii. In a normal brain, synapses can get stronger when a presynaptic cell repeatedly causes a postsynaptic cell to depolarize (we call this long-term potentiation, or LTP). Explain how long term potentiation works including the following details. (3 points)
- Name the neurotransmitter that is released by the presynaptic cell.
- Name the receptor that this neurotransmitter binds to on the postsynaptic cell to mediate normal excitatory transmission.
- What other receptors are involved and how do they get recruited?
- List one way in which the presynaptic neuron changes and one way in which the postsynaptic neuron changes during LTP.

iv. Given what you know about plasticity, could Xaelenfal effect the ability of synapses to potentiate. Explain your answer. (2 points)

Answer 1

AMPA receptors are ion channels localized to excitatory synapses in the central nervous system that mediate fast (millisecond time scale) excitatory neurotransmission. In excitatory neurons, action potentials evoke the release of glutamate from presynaptic terminals at synapses onto postsynaptic excitatory and inhibitory neurons. Synapses onto excitatory neurons are predominantly located on dendritic spines whereas excitatory synapses onto inhibitory interneurons are located on the aspiny dendritic shafts typical of these cells. In either case, the glutamate released from the excitatory neuron axon terminals diffuses across the synaptic cleft and binds to AMPA receptors in the postsynaptic membrane. The AMPA receptors are large multisubunit protein complexes that span the membrane and have an ion-selective central pore that in the absence of glutamate is closed to ion flow. Binding of glutamate causes the AMPA receptors to gate open, which allows cations to flux across the postsynaptic membrane,resulting in a brief depolarization known as the excitatory postsynaptic potential (EPSP). Although AMPA receptors are permeable to sodium, potassium and in some cases also calcium, at resting potential sodium is the main carrier of the depolarizing current. Summation of EPSPs leads to the firing of action potentials by the postsynaptic neuron, completing the transmission of the synaptic signal. Given their role in fast excitatory signaling in the brain, AMPA receptors are a critical component of all neuronal networks. AMPA receptors are as fundamental to brain function as sodium channels but it is important to appreciate the distinction between the two. AMPA receptors mediate synaptic signaling whereas sodium channels are responsible for a neuron’s intrinsic excitability. In line with their distinct functions, sodium channels are voltage-gated and they open in response to membrane depolarization. In contrast, AMPA receptors are largely insensitive to membrane

potential; as neurotransmitter-gated channels, their opening is controlled by a chemical signal — glutamate, the universal chemical messenger for fast excitatory neurotransmission.