Mouse ‘models’ for psychiatric disorders, strains of mice genetically engineered by ‘knocking out’ a specific gene that mediates expression of the disorder, provide invaluable information regarding the genetic, developmental, physiological, and neurological causes of mental diseases in humans.  One of the first mouse models relevant to autism was generated via knockout of a gene called FMR1, whose loss of function in humans causes an autistic spectrum condition called Fragile X syndrome (Kooy et al. 1996; Hagerman et al. 2009).

Amazingly, such mice can now be ‘rescued’ – that is – restored to essentially normal function for cognitive tasks that were formerly much impaired, via treatment with drugs that down-regulate one of their brain receptors for glutamate, called mGLUR5 (Dölen et al. 2007; Hagerman et al. 2009).  Fragile X mice can also be rescued by knocking out one copy of the actual gene that codes for mGLUR5, which reduces the brain’s production of this receptor and thus mimics the impact of pharmaceutical treatment (Dölen et al. 2007).

Drugs that modify function of the mGLUR5 receptor work by normalizing a pathway – a set of interacting, cascading biomolecules in the brain – that was dysregulated by loss of the protein product generated by FMR1.  Such pathways represent intricate, dynamic systems of negative and positive feedback that mediate how we think, learn, feel, and forget, via collective modifications of neuronal structure and function.  Drugs for human psychiatric disorders work by modulating pathways, so understanding such systems is the key to rational discovery of new drugs.

A recent study by Laura Pacey and others at the University of Toronto has demonstrated another way to modify the pathways disrupted by loss of FMR1 function in mice – they found that a key phenotype of FMR1 mice, a propensity to epileptic seizures induced by noise, could be significantly and substantially reduced by knocking out the mice for a second gene, a gene called RGS4.  What’s deeply curious about RGS4 is that reduced expression of this gene, and genetic variants that reduce its function, have been strongly associated with increased risk of schizophrenia (e. g., Chowdari et al. 2008).  In essence, the ‘autistic’ mice were rescued, at least with regard to the seizure phenotype, by making them relatively ‘schizophrenic’.

Molecular neurophysiology is dizzyingly complex, but biological function is ruled by forces of homeostasis and canalization that keep our neuronal wetware working more or less stably.

Can key pathways underlying neuronal function and cognition, and the brain’s equilibria, become dysregulated in two opposite directions, towards autistic phenotypes on one hand and schizophrenic ones on the other (Crespi and Badcock 2008)?  If so, drug discovery for treating both autism and schizophrenia, in both mice and man, might be greatly accelerated.

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Chowdari KV, Bamne M, Wood J, Talkowski ME, Mirnics K, Levitt P, Lewis DA, Nimgaonkar VL. (2008) Linkage disequilibrium patterns and functional analysis of RGS4 polymorphisms in relation to schizophrenia. Schizophr Bull. 34:118-26.

Crespi B. J. and C. Badcock (2008) Psychosis and autism as diametrical disorders of the social brain. Behavioral and Brain Sciences 31: 284-320.

Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF. (2007) Correction of fragile X syndrome in mice. Neuron 56:955-962.

Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M. (2009) Advances in the treatment of fragile X syndrome.  Pediatrics 123:378-390.

Kooy RF, D’Hooge R, Reyniers E, Bakker CE, Nagels G, De Boulle K, Storm K, Clincke G, De Deyn PP, Oostra BA, Willems PJ. (1996) Transgenic mouse model for the fragile X syndrome. Am J Med Genet. 64:241-245.

Pacey LK, Heximer SP, Hampson DR. (2009) Increased GABAB receptor-mediated signaling reduces the susceptibility of Fragile X knockout mice to audiogenic seizures. Molecular Pharmacology (in press).