Presynaptic ionotropic receptors, when activated, directly modify the electrical properties of the presynaptic terminal. This leads to rapid transient changes in the probability of vesicle release, although these effects can also last longer. Activation of an ionotropic receptor triggers the opening of channels in the presynaptic terminal, resulting in the alteration of transmitter release by an action potential.

Presynaptic inhibition occurs when presynaptic receptors binding leads to a decrease in transmitter release. This can be due to various mechanisms. Firstly, the opening of channels reduces membrane resistance and creates a current shunt. This shunt diverts the current associated with the action potential from the active zone membrane, thereby reducing the depolarization of the active zone. Consequently, there is less activation of calcium channels, decreased calcium entry, and subsequently, less transmitter release. Secondly, the opening of presynaptic ionotropic channels causes a change in the membrane potential. This change may result in the inactivation of voltage-gated sodium channels, reducing the current associated with the action potential and transmitter release. Presynaptic γ-aminobutyric acid A receptors (GABAA) in the spinal cord control chloride channels, which generate a hyperpolarization. However, in the presynaptic terminal, the concentration gradient of chloride ions (Cl-) causes an efflux of Cl-, generating a small depolarization. This depolarization is not significant enough to activate voltage-gated calcium channels, preventing an increase in transmitter release. In contrast, other receptors that control cation channels induce large depolarizations, leading to increased transmitter release. Additionally, presynaptic nicotinic acetylcholine receptors control a calcium-permeable cation channel, allowing extra calcium entry and enhancing transmitter release from the terminal.

Repetitive stimulation of specific synapses in the brain can produce persistent changes in the transmission efficacy at those synapses. This phenomenon, known as long-term potentiation or long-term depression, can last for days to weeks and is thought to play a role in memory storage.
In contrast, activation of presynaptic ionotropic receptors will directly alter the electrical properties of the presynaptic terminal and cause rapid transient (millisecond time scale) changes in the probability of vesicle release (although they too can have much longer lasting effects). Binding of an ionotropic receptor will open channels in the presynaptic terminal and thereby alter the amount of transmitter released by an action potential.
Presynaptic inhibition refers to occasions when binding of presynaptic receptors leads to a decrease in release of transmitter, and it can be the result of one or more mechanisms (Fig. 6.10 ). First, opening of channels decreases membrane resistance and creates a current shunt. The shunt acts to divert the current associated with the action potential from the active zone membrane and thereby lessens the depolarization of the active zone, which results in less activation of Ca++ channels, less Ca++ entry, and less release of transmitter. A second mechanism is the change in membrane potential caused by the opening of presynaptic •Fig. 6.10 Presynapticinhibition.Activeregenerationofactionpotentialsinaxon2endsatthelastnode.Theactionpotentialisthenpassivelyconductedintotheterminal.Axon1makesanaxoaxonicsynapsewithaxon2.Activationofthissynapsereducesconductionoftheactionpotentialinaxon2totheactivezoneofitssynapticterminalbymechanismsdescribedinthetext.Thisreducestheopeningofvoltage-gatedCa++ channelsandthereforereleaseofneurotransmitter.
ionotropic channels. If a small depolarization is the result, there will be inactivation of voltage-gated Na+ channels and thereby lessening of the action potential–associated current and transmitter release. Presynaptic γ-aminobutyric acid A receptors (GABAA) occur in the spinal cord and mediate presynaptic inhibition by these mechanisms. They control Cl− channels. Generally, opening of Cl− channels generates a hyperpolarization. However, in the presynaptic terminal, the [Cl−] gradient is such that Cl− flows out of the cell and generates a small depolarization. This depolarization is small enough that it does not cause significant opening of voltage-gated Ca++ channels; otherwise, it would increase release of transmitter (presynaptic facilitation). In fact, there are other receptors that control cation channels and create large depolarizations, thereby increasing the release of transmitter. In addition, presynaptic nicotinic acetylcholine receptors control a cation channel that is permeable to Ca++ . By allowing additional entry of Ca++ , these receptors increase the release of transmitter from the terminal.
Repetitive stimulation of certain synapses in the brain can also produce more persistent changes in the efficacy of transmission at these synapses, a process called long-term potentiation or long-term depression. Such changes can persist for days to weeks and are believed to be involved in the storage of memories.