2002). There is evidence that Rac1/Rho activity has common effects coordinated with that of
FMRP by an intermediary CYFIP protein in mammals and flies (Bardoni and Mandel, 2002;
Schenck et al., 2003). FMRP also interacts with a Rac1 effector, p21-activated kinase (PAK), a
dominant negative transgene of which has produced a substantial reversion of the FX mouse
phenotype (Hayashi et al., 2007). Rho-mediated signaling leads to reorganization of the actin
cytoskeleton, in particular causing neurite retraction in some assays; one of the most prominent
effects of FXS on neurons is on altered synaptic spine morphology (Comery et al., 1997; Hinton
et al., 1991). Furthermore, several known X-linked mental retardation genes are linked to
Rho/Rac GTPase signaling (Bardoni and Mandel, 2002). One of the neurotransmitters that acts
through Gα12∕13 receptors is the monoamine serotonin, which as noted above may be
disregulated in FXS.
(**) Supplemental Text 2
The lack of tolerance to lithium in FX mice is in accordance with its long history of use
without the development of tolerance in psychiatric patients. In contrast, tolerance was to the
other GSK3 inhibitors was evident in FX mice. This may be due to pharmacokinetic changes
with repeated administration or to their ATP-competitive mechanism of inhibition of GSK3, but
there is little in vivo data on which to base speculation about possible mechanisms.
(***) Supplemental Text 3
In addition to CREB, GSK3 phosphorylates translation factor eIF2B. eIF2B inhibition by
GSK3 phosphorylation leads to a reduction in Met-tRNA loading onto the 40S ribosomal