Over the past five years, the core symptoms of autism spectrum disorders have been associated with a wide range of gene mutations. Many of the genes encode proteins of neurons in the brain involved in the formation of synapses, that is, those structures that allow neurons to communicate with each other. This system of connections is essential for the appropriate functioning of the brain, the ability to learn in the memory, the determination of the body movement and the integration of sensory inputs. It has been known for some years that genetic mutations frequently found in relational and intellectual developmental disorders are able to significantly reduce the communication between brain cells. In fact, it is progressively observed that more than a hundred genetic disorders are associated with an autistic phenotype through distinct mechanisms but all more or less directly involved in the development or functioning of the synapses. These gene’s function may be altered even indirectly because of the interaction of the genetic architecture with the environment, through a complexity of mechanisms named epigenetic modifications. As repeatedly communicated in previous publications of this website, one of the most studied genes was the SHANK3 (SH3 and multiple ankyrin repeat domains 3). It is located on chromosome 22 and encodes a protein of the same name, also known as ProSAP2 (Proline-rich synapse-associated protein 2), which is involved in synapse formation and maturation of dendritic spines but also in the connection of various neurotransmitter receptors, channels ionic surfactants and other membrane proteins to the actin cytoskeleton and the signaling pathways linked to protein G. SHANK3 was altered repeatedly in 22q13 deletion syndrome (Phelan-McDermid syndrome) in autism spectrum disorders, schizophrenia and intellectual disability. In 2011, the effects of mutations in different sites of the SHANK3 gene have been studied in both animal models and in vitro. In mice there was a significant impact on social behavior and the neuronal cultures with an additional copy of the gene showed an increase of electrical activity, the number and size of dendritic spines. A first attempt to pinpoint the specific function of SHANK3 was done by the Institute of Neuroscience CNR. The researchers noted that this group of neurons in which the expression of SHANK3 was blocked by inhibitors of RNA on the membranes showed a selective reduction in synaptic glutamate receptor type 5 (mGluR5). The fascinating journey from these early discoveries to the most recent group of New Zealand will be discussed in the second part.
REFERENCES
- Arons MH, Thynne CJ, Grabrucker AM, Li D, Schoen M, Cheyne JE, Boeckers TM, Montgomery JM, Garner CC. Autism-Associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin-Neuroligin-Mediated Transsynaptic Signaling. J Neurosci, 2012 Oct 24; 32(43): 14966-78.
- Durand CM, Perroy J, Loll F, Perrais D, Fagni L, Bourgeron T, Montcouquiol M, Sans N. SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Mol Psychiatry, 2012 Jan;17(1):71-84.
- Herbert MR. SHANK3, the synapse, and autism. N Engl J Med. 2011 Jul 14;365(2):173-5. Erratum in: N Engl J Med. 2011 Nov 10;365(19):1848.
- Verpelli C, Dvoretskova E, Vicidomini C, Rossi F, Chiappalone M, Schoen M, Di Stefano B, Mantegazza R, Broccoli V, Böckers TM, Dityatev A, Sala C. Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses. J Biol Chem. 2011 Oct 7;286(40):34839-50.