Fragile x syndrome and autism: from disease model to therapeutic targets
© Springer Science + Business Media, LLC 2009
Received: 7 February 2009
Accepted: 29 April 2009
Published: 12
Fragile x syndrome and autism: from disease model to therapeutic targets
© Springer Science + Business Media, LLC 2009
Received: 7 February 2009
Accepted: 29 April 2009
Published: 12 May 2009
Autism is an umbrella diagnosis with several different etiologies. Fragile X syndrome (FXS), one of the first identified and leading causes of autism, has been modeled in mice using molecular genetic manipulation. These Fmr1 knockout mice have recently been used to identify a new putative therapeutic target, the metabotropic glutamate receptor 5 (mGluR5), for the treatment of FXS. Moreover, mGluR5 signaling cascades interact with a number of synaptic proteins, many of which have been implicated in autism, raising the possibility that therapeutic targets identified for FXS may have efficacy in treating multiple other causes of autism.
KeywordsFragile X FXS Metabotropic Glutamate Receptor mglur mglur5 FMRP Fragile x mental retardation protein Synaptic plasticity Long term depression LTD Protein synthesis Translation Ocular Dominance Plasticity Visual Cortex Hippocampus Inhibitory avoidance Passive avoidance Extinction Autism HOMER SHANK Neuroligin Neurexin Tuberous sclerosis TSC TSC1 TSC2 Rett MeCP BDNF PTEN Hamartoma Angelman UBE3 Dendritic spine Synapse Development Synapsopathy Audiogenic seizure Seizure Mental retardation Cognitive Impairment
Leo Kanner first described autism in 1943. It wasn’t until 1980 however, that autism was formally recognized in the Diagnostic and Statistical Manual of Mental disorders (DSM-III), and included as part of a new class, the Pervasive Developmental Disorders (PDD). At the same time, early psychodynamic theories of the etiology of autism  were being abandoned in favor of genetic ones. As early as 1975, case reports of monozygotic twins concordant for autism, followed by several systematic twin studies [5–10] substantiated the strong heritability of autism [11–13].
Standardization of diagnostic criteria, and improvements in our ability to reliably detect chromosomal abnormalities  allowed for the identification in the early 1980’s of the first genetic cause of autism—Fragile X syndrome (FXS) [15–17]. Subsequently, the Fragile X gene (FMR1) was discovered, and by 1994 the first animal model became available. This genetically engineered Fmr1 knockout mouse (Fmr1 KO), has been validated for FXS, and is currently one of the leading animal models of autism.
Using this mutant mouse, we have been able to address the role of the FMR1 gene and the protein it encodes (fragile X mental retardation protein, FMRP) in brain development. Now, over 25 years since FXS was identified as a cause of autism, a new putative therapy has been proposed based on our understanding of the function of FMRP.
Modeling autism: a derailment of synaptic plasticity
Inherited mutations have the potential to disrupt brain development from the moment of fertilization onward; however, a genetic etiology does not preclude pathogenesis involving regulated processes later in development. Symptoms of autism typically present during the early postnatal period, usually between ages 1–3 years. This epoch, the so-called ‘critical period’, corresponds to a dynamic phase of brain development in which neurite outgrowth, maturation of inhibition and signaling, axon myelination, and synaptic plasticity are set in motion by the complex interplay of molecular genetic programs and experience. Disruption of any of one of these processes could hypothetically lead to the characteristic symptoms of autism, which include abnormal social interaction and communication, stereotyped repetitive behaviors, often with co-morbid mental retardation, epilepsy, sleep disturbances, attention deficit and hyperactivity. Th