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Synapses and Neuromodulation


The current understanding of nervous system function holds a prominent place for the role of neuromodulators in shaping electrophysiological activity. All functions of the nervous system, which ranges from simple reflection to sleep, memory and higher cognitive tasks, are ultimately caused by the activity of neural circuits. A wide variety of substances, including small molecule transmitters, biogenic amines, neuropeptides and others can be released in ways other than the classical fast synaptic transmission. One of these mechanisms is known to be neuromodulation.

Neuromodulators are often thought to convey global control of brain states that underlie different behaviors, such as sleep and arousal. Studies show that multiple neuromodulators can act on any single neuron at the same time, and the intrinsic excitability and synaptic efficacy are always affected by neuromodulation. Therefore, the reconfiguration of neural circuits by neuromodulators is a complex balancing process, involving multiple synergistic or antagonistic approaches.

Definition / general explanation:

Synapse: In the central nervous system, a synapse is a small gap at the end of a neuron, allowing electrical signals to be transmitted from one neuron to another. Synapse is the key to brain function, especially in memory.


Neuromodulation is the process of regulating nervous activity by controlling the physiological levels of several classes of neurotransmitters.


Synapse, also known as the neuronal junction, is a place where nerve electrical impulses are transmitted between two nerve cells (neurons) or between a neuron and a gland or muscle cell (effector). A synaptic connection between a neuron and a muscle cell is called a neuromuscular junction.

Neuromodulators: Link.

A neuromodulator is a chemical messenger released from a neuron in or around the central nervous system, which affects different groups of neurons with appropriate receptors. Neuromodulators are a subset of neurotransmitters.

The function of neuromodulation is to change the signal transmission strength between neurons. They do this by controlling the number of neurotransmitters synthesized and released by neurons. In fact, neuromodulators have a longer range of action compared to regular neurotransmitters. That is, the release of neuromodulators can influence both neurons near and far from the site of release.

It is worth noting that neuromodulators are binded to metabotropic receptors. Metabotropic receptors are types of membrane receptors that use signal transduction mechanisms to activate many intracellular events. They have a slow-acting effect and sensitize/desensitize neurons by changing the strength of signal transmission between neurons.


Neurotransmitters are chemical messengers released from the nerve ends of a neuron, which are used to communicate with adjacent neurons. (A presynaptic neuron transmits the signal toward a synapse, whereas a postsynaptic neuron transmits the signal away from the synapses). The neurotransmitters are released by presynaptic neurons, and either excite or inhibit the postsynaptic neuron.

After release, the neurotransmitters are removed, which can occur by one of 3 mechanisms. Neurotransmitters can either be quickly degraded in the synaptic cleft (Synaptic cleft is the space that separates a neuron and its target cell at a chemical synapse), taken back up (this is called “reuptake”) by the presynaptic neuron, or taken up into adjacent glial cells. This is necessary to limit the amount of time they are in the synaptic cleft, so that other nerve impulses can be communicated. The neurotransmitters that are reuptaken will be recycled and reused.

The Importance of the Receptors

The type of receptor that a chemical interacts with determines whether it is considered a neurotransmitter or a neuromodulator. Because the receptors can determine whether the same chemical is to be a fast-acting neurotransmitter or a slow-acting neuromodulator.

The difference between neuromodulators and neurotransmitters:


  • A chemical messenger released from a neuron in or around the central nervous system, which affects different groups of neurons with appropriate receptors.

  • Used to change the strength of signal transmissions between neurons

  • Has a large range of influence on neurons

  • Subset of neurotransmitters

  • A longer range of action

  • Release of neuromodulators occurs in a diffuse manner (“volume transmission”)

  • Longer lasting than regular neurotransmitters

  • Different type of neuroreceptors


  • A chemical messenger released from the nerve ending of a neuron

  • Used to communicate with adjacent neurons

  • Only one presynaptic neuron directly influences a single postsynaptic neuron near it.

  • A shorter range of action

  • Release of neurotransmitters occurs with vesicle transport

  • Different type of neuroreceptors

Fun Fact:

  • There are specific neurotransmitters that have been categorized as neuromodulators because they almost always work in the way described by #1 and #2. These are: dopamine (D receptors), serotonin (5HT receptors), acetylcholine (M and nicotinic receptors), noradrenaline (alpha and beta receptors), and histamine (H receptors). These neurotransmitters tune the functioning of neural circuits in neural tissue rather than sending signals directly into particular neurons

  • The act of neuromodulation, unlike that of neurotransmission, does not necessarily carry excitation of inhibition from one neuron to another, but instead alters either the cellular or synaptic properties of certain neurons so that neurotransmission between them is changed.

Neuromodulation of Synapses:

Neuromodulators change synaptic communication through a variety of mechanisms, which can be roughly divided into direct effects on synapses and indirect effects on synaptic interactions by changing the excitability of neurons. Indirect effects include presynaptic modulation, which can lead to changes of action potential shape, and postsynaptic regulation, such as increasing voltage-gated inward current to enhance EPSPs. Direct effects on synaptic interactions can also be divided into pre- and postsynaptic mechanisms.

Synaptic Transmission:

Synaptic transmission is the biological process by which a neuron communicates with a target cell through synapses. Chemical synaptic transmission involves the release of a neurotransmitter from the presynaptic neuron, and neurotransmitter binding to specific post-synaptic receptors.

Neuromodulation vs Synaptic Transmission:


  • Neuromodulation happens when a substance released from a neuron alters the cellular or synaptic properties of another neuron

  • The local postsynaptic receptors are G-protein coupled receptors

  • Their neurotransmission is slow

Synaptic Transmission

  • During regular synaptic transmission, one presynaptic neuron directly influences a single postsynaptic neuron.

  • The post synaptic receptors are ligand-gated ion channels

  • Their neurotransmission is fast.

Besides neurotransmitters and neuromodulators, there are also neurohormones found in the central nervous system.


A neurohormone is a kind of chemical messenger released by neuroendocrine cells. Neuroendocrine cells are cells that receive input from neurons like neurotransmitters, and in response, release messenger molecules, like hormones, into the bloodstream. By releasing the hormones into the blood, neurohormones can act on peripheral targets far away.

An example of a neuroendocrine cell is the cells of the adrenal medulla, which is the innermost part of the adrenal gland. The adrenal medulla releases adrenaline into blood in response to stimulation by sympathetic preganglionic neurons, which are neurons of the autonomic nervous system. The difference between neuromodulators and hormones is that the extent of actions vary between the two.

Fun fact:

Hormones last up to 10 times longer than neurotransmitters!


Britannica. (2020). Synapse | anatomy | Britannica. In Encyclopædia Britannica. Retrieved from

Khetrapal, A. (2009, November 17). What is Neuromodulation? Retrieved December 29, 2020, from website:

Lee, S. (n.d.). Neurotransmitters VS Neuromodulators. Retrieved December 29, 2020, from The Revisionist website:

Nadim, F., & Bucher, D. (2014). Neuromodulation of neurons and synapses. Current Opinion in Neurobiology, 29, 48–56.

Neuroscientifically Challenged. (2014, July 22). 2-Minute Neuroscience: Synaptic Transmission. Retrieved December 29, 2020, from YouTube website:

Synaptic transmission - Latest research and news | Nature. (n.d.). Retrieved December 29, 2020, from website:

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