Excitatory and Inhibitory Synaptic Signalling

Neurones talk to each other by passing chemical signals called neurotransmitters across small gaps known as synapses.  Presynaptic neurones release neurotransmitters which then diffuse across the synapse before binding to the receptor on the postsynaptic neurone. This process is called synaptic transmission.

The binding of a neurotransmitter to its corresponding receptor exerts specific effects on the postsynaptic cell, for example by influencing its membrane potential. Accordingly, we can broadly divide neurotransmitters into excitatory and inhibitory.

This article will explore how excitatory and inhibitory neurotransmitters work on the molecular level and how neurones integrate all incoming signals. Lastly, we will have a look at what happens when the balance between excitation and inhibition goes wrong.

Synaptic Transmission – a Snapshot

First, let’s remind ourselves what are the stages of synaptic transmission, using the example of acetylcholine:

• Synthesis of acetylcholine occurs in the presynaptic neurone
• Acetylcholine is stored in vesicles within the presynaptic neurone
• The influx of calcium ions following the depolarization of the presynaptic terminal initiates the fusion of vesicles with the presynaptic membrane
• Neurotransmitter is released into the synaptic cleft by a process known as exocytosis
• Neurotransmitter diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors on the postsynaptic membrane
• Acetylcholine is broken down by acetylcholinesterase into choline and acetate
• Choline is taken up by the presynaptic neurone for further production of acetylcholine

vectorization: Mouagip (talk)Synapse_diag1.png: Drawn by fr:Utilisateur:DakeCorrections of original PNG by en:User:Nrets This W3C-unspecified vector image was created with Adobe Illustrator., CC BY-SA 3.0 , via Wikimedia Commons

Fig 1 – Diagram showing the basic model of neurotransmission. (A) Presynaptic neuron. (B) Postsynaptic neuron. (1) Mitochondria. (2) Synaptic vesicles containing neurotransmitters. (3) Autoreceptor. (4) Synaptic cleft. (5) Neurotransmitter receptor. (6) Calcium channel. (7) Fused vesicle releasing neurotransmitter. (8) Neurotransmitter reuptake pump.

Excitatory and Inhibitory Synaptic Signalling

Neurotransmitters can be broadly divided into excitatory and inhibitory:

• Excitatory neurotransmitters increase the likelihood of postsynaptic neurone depolarization and generation of an action potential
• Inhibitory neurotransmitters reduce the likelihood of postsynaptic neurone depolarization and generation of an action potential.

An example of an excitatory neurotransmitter is glutamate, whereas GABA is an inhibitory neurotransmitter. Some neurotransmitters, including dopamine, may exert both excitatory and inhibitory effects by binding to different receptors. Now, let’s have a look at what happens at the molecular level when an excitatory or an inhibitory neurotransmitter binds to its postsynaptic receptor.

Postsynaptic Potential

Ionotropic receptors are one class of postsynaptic receptors. These proteins incorporate an ion channel within their molecular structure. When a neurotransmitter binds to its postsynaptic receptor it causes ion channels to open, or less frequently, to close. This movement of ions across the neuronal membrane generates an electrical current, the postsynaptic current (PSC), which in turn changes the postsynaptic membrane potential to produce a postsynaptic potential (PSP).

In contrast to action potentials, postsynaptic potentials are not all-or-nothing phenomena of a constant magnitude but rather graded changes, dependent upon the magnitude of ion flow across the membrane. Similarly to neurotransmitters, PSPs are divided into:

• Excitatory postsynaptic potentials (EPSPs) increase the likelihood of a postsynaptic action potential occurring and are induced by excitatory neurotransmitters.
• Inhibitory postsynaptic potentials (IPSPs) decrease the likelihood of a postsynaptic action potential occurring and are induced by inhibitory neurotransmitters.

Next, we will analyse in detail how neurotransmitters induce PSPs.

Excitatory Synaptic Signalling

Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. It exerts its effects via ionotropic receptors such as kainate, AMPA or NMDA receptors as well as metabotropic receptors – mGlu1-mGlu8. Let’s see what happens when glutamate molecules bind to an AMPA receptor.

Upon binding of glutamate molecules to an AMPA receptor, its integral ion channel opens and ions flow across the postsynaptic neuronal membrane. AMPA receptor is a non-selective cation channel, which is mostly permeable to sodium and potassium ions. The direction and magnitude of ionic flow across the membrane depends on the postsynaptic membrane potential and concentrations of sodium and potassium across the membrane.

Let’s assume that the postsynaptic membrane potential is  -80mV. After the opening of an AMPA ion channel, sodium ions will flow into the postsynaptic cell according to their concentration gradient. They will be also ‘attracted’ into the neurone by the negative charge of the postsynaptic neurone.

Conversely, as the postsynaptic membrane potential is close to the potassium equilibrium potential, the driving force for the potassium ions will not be very significant – the potassium ions will be leaving the cell according to their concentration gradient but simultaneously they will be attracted by the negative charge of the postsynaptic neurone.

Isaac Webb, CC BY-SA 3.0 , via Wikimedia Commons

Fig 2 – Diagram showing a closed ion channel on the left and an open channel on the right once the ligand has bound. (1) Ion channel. (2) Ions. (3) Ligand.

In summary, the electrochemical gradient driving sodium ions into the cell is stronger than the gradient driving potassium ions out of the cell. Consequently, the resultant sodium current leads to changes in the membrane potential, an excitatory postsynaptic potential (EPSP), which makes the membrane potential more positive. Hence, EPSP brings membrane potential closer to the threshold needed for an action potential generation.

To find out more about equilibrium potentials and electrochemical gradients please read our article on Resting Membrane Potential.

Inhibitory Synaptic Signalling

Now let’s take a look at the effects of an inhibitory neurotransmitter. GABA is the major inhibitory neurotransmitter in the mammalian nervous system. Similarly to glutamate, it acts via ionotropic receptors – GABA_A receptors– as well as metabotropic receptors – GABA_B receptors.

The binding of GABA to GABA_A receptors induces the opening of ion channels that are selectively permeable to chloride ions. Consequently, GABA causes chloride ions to flow across the postsynaptic membrane. As chloride ions are more abundant extracellularly, they will flow down their concentration gradient into the cell, producing a hyperpolarising current and hence generating a hyperpolarising inhibitory postsynaptic potential.

This IPSP will take the postsynaptic membrane away from the action potential threshold, thus inhibiting the postsynaptic cell.

Temporal and Spatial Summation

One neurone can receive thousands of synaptic inputs. Hence, the impact of this multitude of signals on a single neurone – whether an action potential will be generated or not – is determined by the summation of all the IPSPs and EPSPs.

Gth768r, CC BY-SA 3.0 , via Wikimedia Commons

Fig 3 – Summation of EPSPs and IPSPs.

There are two types of inputs summation used by the neurones:

• Spatial summation involves the integration of signals coming from multiple presynaptic neurones simultaneously. For example, the greater the number of EPSPs, the greater the chance of the threshold being achieved. Conversely, the greater the number of IPSPs, the lower the chance of the threshold being achieved.
• Temporal summation involves the integration of signals (EPSPs or IPSPs) separated in time. For example, the smaller the time interval between EPSPs, the greater the cumulative increase in the postsynaptic potential, thus increasing the likelihood of the threshold being met.