Provided by Cognitive Sciences ePrint Archive
Supplemental Text
(*) Supplemental Text 1
A more specific means by which FX GSK3 activity might be elevated is suggested by up-
regulation of monoamine activity in the FX fly model (Zhang et al., 2005) as well as alterations
in markers of monoamine synthesis in the FX mouse (Gruss and Braun, 2004). Dopamine
elevations in the FX brain may contribute to hyperarousal, and possibly even cognitive
symptoms, as elaborated by Zhang et. al. (2005). The phenotypes studied here, especially
locomotor behavior in the open field, would also be likely impacted by elevated dopamine levels.
Of particular note, amphetamines, known to interfere with dopamine uptake, produce an
elevation of GSK3β Ser-9 phosphorylation in wild-type mice (via D2R inhibition of Akt)
(Beaulieu et al., 2004). Therefore, elevated dopaminergic signaling could be one cause of
elevated GSK3 activity in the FX brain. It has also been demonstrated that DHPG-induced
mGluR group I signaling can produce enhanced dopamine release (Pintor et al., 2000) and that
dopamine is required in the nucleus accumbens for mGluR stimulated locomotion (Meeker et al.,
1998). Muscarinic inputs can have similar effects to glutamate on dopaminergic neurons (Grace,
2002), consistent with recent findings that muscarinic acetylcholine receptor-mediated LTD is
altered in the FX mouse hippocampus (Volk et al., 2007). Therefore, a number of
neurotransmitter signaling alterations described in the FX brain could exert a stimulatory effect
on GSK3, albeit in a more indirect and circuit-based manner than localized to single-cell-based
linear mGluR group I biochemical pathways.
Another possibly related means by which GSK3 has been found to be activated in
neuronal cells is via Gα12 and Gα13 signaling, with the latter being Rho-mediated (Sayas et al.,