Neurotransmitters are endogenous molecules released by neurons and are the primary units of electrochemical signaling between neurons at synapses.


The following are the classic criteria for a neurotransmitter, which are based on the properties of the first identified neurotransmitter, acetylcholine1. However, these criteria are not strictly adhered to in practical usage. A number of substances that do not fulfill all the criteria are still widely accepted as neurotransmitters2,3:

  • The enzymes involved in the synthesis of the substance must be present within the presynaptic neuron.
  • The substance must be released from axon terminals when the presynaptic fibers are stimulated.
  • The action of the substance when applied to the postsynaptic cells must accurately mimic that seen during normal synaptic transmission.
  • A mechanism must be present at the site of the synapses to terminate the action of the putative transmitter.
  • The effect of drugs (i.e., agonists or antagonists) on the postsynaptic cells must be the same when the putative transmitter substance is applied to the synapse.
  • The postsynaptic cells must bear the appropriate receptors for the substance.

Synaptic transmission:

Sufficient depolarization of the presynaptic terminal by innervating action potentials can trigger exocytosis of a neurotransmitter into the synaptic cleft. As the neurotransmitter diffuses across the cleft, a proportion of neurotransmitter may bind and activate postsynaptic receptors.

These receptors may be ionotropic (directly opens or closes an ion channel), or metabotropic (activation of an ion channel is indirect via intracellular signaling molecules, including G-proteins).

Receptor binding results in either excitatory or inhibitory postsynaptic potentials; the net effect of multiple activated inputs may result in initiation of action potentials in the postsynaptic neuron, and thus, the ‘message’ is transmitted from the pre- to postsynaptic neuron4.

Relevance to autism:

Glutamate is the principal excitatory neurotransmitter in the brain with an estimated 50 percent or more of synapses utilizing the neurotransmitter. In recent years, it has been shown that glutamate released by astrocytes can also modulate neuronal transmission. Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain occupying 25-40 percent of synapses in the brain, depending on brain region5.

An imbalance in synaptic excitation and inhibition is thought to contribute to the pathophysiology of autism spectrum disorders6,7.

The FMRP protein, which is lacking in fragile X syndrome, regulates the metabotropic glutamate receptor 5 (mGLuR5). Deletion of one copy of the mGluR5 gene reverses many of the autism-like symptoms in the fragile X knockout mouse.

Antagonists to mGluR5 are being investigated as possible therapeutics for autism spectrum disorders, although early results indicate the picture may be more complicated than originally thought.

Reduced GABA transmission can also shift the balance to hyper-excitability, and support for dampened GABA function has come from a number of studies, including genetic analysis of families with autism, histology mapping of GABA-related proteins8, and in a mouse model of Rett syndrome.

The neuropeptide oxytocin has also been implicated in autism. Most oxytocin neurons are located in the paraventricular nucleus of the hypothalamus and are key regulators of the neuroendocrine system.

Although oxytocin has direct actions on neurotransmission, it is often considered a neuromodulator because it can modify glutamate and GABA signaling9Oxytocin generally has ‘pro-social’ effects10, and seems to mediate key elements of attachment11 and social recognition12 in animals and humans.

Because social impairments are a core feature of autism, there is much research on whether oxytocin dysregulation contributes to the pathophysiology of autism. A compelling report shows that intranasal administration of oxytocin increases trust in humans13. Oxytocin is being investigated as a possible therapeutic for autism14 as well as other psychiatric disorders15.

  1. Cowan W.M. et al. Synapses. Johns Hopkins University Press (2001)
  2. Kreitzer A.C. Curr. Biol. 15 R549-51 (2005)
  3. Snyder S.H. and C.D. Ferris Am. J. Psychiatry 157, 1738-51 (2000)
  4. Kandel E.R. et al. Principals of Neural Science, 4th edition. McGraw-Hill (2000)
  5. Halassa M.M. and P.G. Haydon Annu. Rev. Physiol. 72, 335-55 (2010)
  6. Rubenstein J. and M. Merzenich Brain 2, 255-67 (2003)
  7. Yizhar O. et al. Nature Epub ahead of print (2011)
  8. Oblak A. et al. Autism Res. 4, 205-19 (2009)
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  10. Kirsch P. et al. J. Neuro. 25, 11489-93 (2005)
  11. Young L.J. and Z. Wang Nat. Neurosci. 10, 1048-54 (2004)
  12. Ferguson J.N. Nat. Genet. 3, 284-8 (2000)
  13. Kosfeld M. et al. Nature 435, 673-6 (2005)
  14. Green J.J. and E. Hollander Neurotherapeutics 3, 250-7 (2010)
  15. Feifel D. et al. Biol. Psychiatry 68, 678-80 (2010)