The British neurophysiologist and Nobel Laureate Sir Charles Sherrington first introduced the term ‘synapse’ in 1897. He described this complex cell-cell contact as a “close connection between two nerve cells simply without the continuity of substance”1.

More recently, several studies have implicated mutations in proteins that function at the synapse in autism, leading experts to refer to autism as a “disorder of the synapse.”

Types of synapses:

Within the mammalian central nervous system there are chemical synapses — the predominant type — and electrical synapses. Chemical synapses can further be subdivided into excitatory —which activate signals in the brain and are again the predominant type — and inhibitory contacts, which dampen signals in the brain.

Synapses are specialized structures containing a presynaptic bouton at the axon terminal of a neuron and the postsynaptic compartment, the dendritic spine, dendritic shaft or soma of another neuron. These two structures are bridged by a small space in between, called the synaptic cleft 2.

Upon activation, the neurotransmitter (a chemical substance) is released from the active zone of the presynaptic bouton into the synaptic cleft by exocytosis3,4. It then diffuses towards the postsynaptic compartment to bind its receptors that are clustered in the postsynaptic density (PSD)5,6.

Among neurotransmitters within the central nervous system, the most common excitatory one is glutamate, whereas γ-aminobutyric acid (GABA) and glycine are the predominant inhibitory ones. Synaptic contacts are stabilized and modulated by a surrounding matrix of cell-adhesion molecules7 and extracellular matrix proteins8.

Chemical synapses can morphologically be classified as Gray type I and Gray type II. Gray type I synapses are asymmetric synapses, excitatory, display a wide synaptic cleft (approximately 20 nanometers), contain small, round neurotransmitter-storing vesicles within the presynaptic bouton and a distinct postsynaptic density located at the tip of a dendritic spine. Gray type II synapses are symmetric synapses, inhibitory, predominantly located at the dendritic shaft, exhibit a smaller synaptic cleft (approximately 12 nanometers), pleomorphic presynaptic vesicles and a less distinct PSD9.

Relevance to autism:

As functional synaptic networks are a fundamental prerequisite for a healthy brain, one can easily imagine that various disturbances at the molecular level might disrupt synaptic circuits and therefore cause key symptoms of neuropsychiatric disease.

Depending on when they appear throughout one’s lifespan, those disturbances can have different impacts on the phenotype. Intriguingly, studies from the past decade have gathered evidence showing that genetic alterations of proteins involved in the formation and maintenance of central nervous system synapses can lead to neurodevelopmental disorders such as mental retardation and autism10.

Studies have linked mutations in several proteins that function at the synapse to autism. A 2003 landmark paper identified mutations in neuroligin 3 or NLGN3and neuroligin 4 NLGN4 in two brothers who had autism. Since then, several studies and mouse models have linked neuroligins and neurexins to autism.

SHANK3, one of the strongest autism-candidate genes, is located at the postsynaptic density, on the receiving end of synapses.

Other synaptic proteins associated with autism include CNTNAP2 and GRIP1.

  1. Foster M. and C.S. Sherrington Michael Foster's Textbook of Physiology 7th Edition London: Macmillan (1897)
  2. Kandel E.R. et al. Principles of Neural Science (4th Edition) New York: McGraw-Hill (2000)
  3. Gundelfinger E.D. et al. Nat. Rev. Mol. Cell Biol. 4, 127-139 (2003)
  4. Sigrist S.J. and D. Schmitz Curr. Opin. Neurobiol. 21, 144-150 (2011)
  5. Boeckers T.M. Cell Tissue Res. 326, 409-422 (2006)
  6. Sheng M. and C.C. Hoogenraad Annu. Rev. Biochem. 76, 823-847 (2007)
  7. Giagtzoglou N. et al. Cold Spring Harb. Perspect. Biol. 1(4) (2009)
  8. Dityatev A. et al. Nat. Rev. Neurosci. 11, 735-746 (2010)
  9. Gray E.G. Nature 183, 1592-1593 (1959)
  10. Toro R. et al. Trends Genet. 26, 363-372 (2010)