Williams Syndrome

the LIMK-1 pathway is one of the specific mechanisms whereby the rho system regulates cytoskeletal structure.

LIMK-1 homozygous knockout mice, as might be expected, have alterations in actin microfilaments owing to derangements of actin turnover (27). They also manifest altered dendritic spine morphology at Schaffer-collateral synapses in the hippocampus. Specifically, they have fewer actin microfilaments than the normally actin-dense spines, and the dendritic spines in LIMK-1 knockout mice lack the normal bulbous ending that dendritic spines exhibit. There are no apparent alterations in synaptic number or baseline synaptic function, however. Like FMR2 knockout mice, LIMK-1 knockouts exhibit LTP that saturates at a higher level than controls—a higher maximal level of potentiation is achieved with repetitive LTP-inducing stimulation.

This alteration in synaptic plasticity is associated with impaired learning as well. Specifically, LIMK-1 knockouts show a decrease in their capacity to "unlearn" the location of a hidden platform in a Morris water maze task after they have learned that a platform is associated with a particular location. This is assessed using a platform reversal variation of the water maze, where the hidden platform is moved to a new location after the animal has been repeatedly trained with the platform in one place. The effects on LTP and dendritic spine morphology in the LIMK-1 knockout mouse suggest a possible basis for the cognitive effects in Williams Syndrome. They also point to the growing understanding of the importance of morphological regulation in learning and synaptic plasticity, including apparently those processes occurring in the human CNS.

of exon 1 of FMR2 is the most common lesion and results in the reduction of FMR2 gene expression. The product of FMR2 is a novel member of a family of proteins, and the gene encodes a 1311 amino acid protein with a predicted molecular mass of 141 kDa. As described in the next paragraph, the current hypothesis for the function of the FMR2 protein is that the protein functions as a transcription factor or transcrip-tional regulator. Adult brain expression studies using Northern blots in mice show high expression of fmr2 (the mouse homologue) in hippocampus and amygdala.

As already mentioned, even though the function of FMR2 has yet to be directly determined, FMR2 is hypothesized to be transcriptional activator. It shares significant homology (20-35% amino acid identity) with three autosomal genes: AF4,

LAF4, and AF5Q31. All four proteins of the FMR2 family share several highly similar regions that are homologous to functional motifs involved in transcriptional regulation. The proteins also exhibit features of proteins involved in transcriptional regulation, such as being rich in serine and proline. In fact, FMR2 protein family members AF4 and LAF4 have been shown experimentally to have a capacity for tran-scriptional transactivation, but this has not yet been tested directly for FMR2 itself.

David Nelson's laboratory at Baylor College of Medicine developed a murine Fmr2 gene knockout model for FRAXE (19). Mice lacking Fmr2 showed impairment of both contextual and cued fear conditioning, suggesting a similarity of learning deficiencies in the mouse and human. The contextual fear impairment was found to be

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