THE MANNER IN WHICH A GENETIC MUTATION MAY LEAD TO AUTISM AND OTHER NEURODEVELOPMENTAL DISORDERS EXPLAINED - PART TWO

 Researchers at the Institute of Neuroscience CNR noted that 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). This determined, in turn, a reduction in the phosphorylation of ERK1 / 2 (extracellular receptor-activated kinase) and CREB (cAMP Response Element-Binding Protein), but especially an impairment of synaptic plasticity and activity of the neural network. Also found were morphological abnormalities in the structure of synapses (number of spines, width and length) and reduction of glutamatergic transmission. The pharmacological enhancement of the activity of mGluR5 represents the normal activity of signaling, showing that they can compensate for the damage caused by mutation of SHANK3. Dr Johanna Montgomery has recently led a group of researchers from the Center for Brain Research at the University of Auckland to discover new dynamics by which alterations of SHANK3 leads to autism and other neurodevelopmental disorders. The first explanation concerns the fact that cells with mutations of SHANK3 not only communicate less with each other, but are also much less able to reinforce the synaptic connection through the repetition of the transmission of the same signal. A second finding concerns the ability of the protein SHANK3 to give life to neurexin and neuroligina complexes which create bridges can cross the synaptic cleft. These bridges lead information on the functioning of synaptic transmission of various signals and are therefore useful precisely to strengthen the connection.

Researchers in New Zealand found that in hippocampal neurons of rattus norvegicus protein SHANK3 (also known as ProSAP2) regulates glutamatergic synaptic transmission (linked to the NMDA receptor) and induces large changes in the levels of pre-and post-synaptic proteins through a process of trans-synaptic signaling mediated by complex neurexin-neuroligina. Mutations in SHANK3 are associated with autism spectrum disorders that alter this complex mechanism of connection and maturation of excitatory synapses in the central nervous system areas fundamental to relational skills. Moreover, these mutations have been found to be associated to other neurodevelopmental and psychiatric disorders, such as Intellectual Disability and Schizophrenia. The data suggest that these alterations in the developmental and neural plasticity processes, with different degrees and intervening in different stages of the development, may be considered the genetic background of different disorders often co-occurring. Dr. Montgomery is confident that these new discoveries over the coming years are likely to promote the development of therapies that limit the alterations of synapses and significantly reduce the disability of people with neurodevelopmental disorders.

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. 

- Sala C, Vicidomini C, Bigi I, Mossa A, Verpelli C. Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders. J Neurochem. 2015 Dec;135(5):849-58. doi: 10.1111/jnc.13232. Epub 2015 Sep 3
- 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.