Lessons From Mutant Animals And Genetic Diseases

The functions of a number of scaffold proteins have been analyzed in knockout mice and, in the case of some actin-binding proteins (such as aA-catenin and spinophilin), a clear phenotype has been identified as a change in dendritic spine morphology and synapse function. Many others will probably soon be available, thus clarifying the relative roles of these proteins in spine structure.

Among the PSD-95 family, the most interesting phenotype observed so far is that of PSD-95 mutant mice, whose spatial learning is impaired although LTP is enhanced and LTD is defective33. The behavioral sensitization induced by chronic cocaine administration is also eliminated in these mice99 and the maturation of orientation preference in the visual cortex fails to mature100. These in vivo results demonstrate that PSD-95 is important for the regulation of synaptic plasticity.

Even more interesting is the observation that PSD-95 may be important for the correct balance of excitatory and inhibitory synapses in brain. A possible mutation of PSD-95 has been found in autistic patients101, and it was proposed that an incorrect balance between excitatory and inhibitory synapses is associated with autism102 (also see Chapter 27).

As mentioned above, a number of genetic diseases involving mental retardation are often correlated with defects in dendritic spine morphology. One form of mental retardation associated with severe expressive language delay and minor facial dysmorphisms has been found in several patients with a 22q13.3 distal deletion that causes Shank3 haploinsufficiency103,104. It is still not known whether these patients have altered synapses and spine morphology, but the presence of this genetic disease in humans strongly suggests that scaffold proteins play a major role in brain function.

Funny Wiring Autism

Funny Wiring Autism

Autism is a developmental disorder that manifests itself in early childhood and affects the functioning of the brain, primarily in the areas of social interaction and communication. Children with autism look like other children but do not play or behave like other children. They must struggle daily to cope and connect with the world around them.

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