Basic research on fragile X syndrome (FXS) is currently entering its third decade.
A wealth of knowledge has been generated concerning the pathophysiology of FXS that
has fueled new treatment strategies. As often happens in any field of biology, some
theories gain more ground than others, which languish many years before an important
study brings it back into the limelight. The most intensely studied theory in FXS
research is the “mGluR theory of FXS” (
Toward fulfilling the promise of molecular medicine in fragile X syndrome.
), which posits that excessive group I metabotropic glutamate receptor (mGluR1/5)–mediated
translation in neurons is responsible for most synaptic and behavioral abnormalities
associated with the syndrome. The focus on targeting mGluR5 in FXS has been extremely
successful in genetic and preclinical studies of animal models and forms the backbone
of current drug initiatives from Novartis (Basel, Switzerland), Roche (Basel, Switzerland),
and other pharmaceutical companies. However, recent studies have discovered that other
cell-surface signal transducers, such as endocannabinoid receptors, also are relevant
to the pathophysiology of FXS (
- Busquets-Garcia A.
- Gomis-González M.
- Guegan T.
- Agustín-Pavón C.
- Pastor A.
- Mato S.
- et al.
Targeting the endocannabinoid system in the treatment of fragile X syndrome.
), arguing for the possibility that not all symptoms associated with FXS are due to
aberrant mGluR signaling. Fragile X syndrome is widely considered to be the leading
inherited cause of autism spectrum disorder and intellectual disability. A fundamental
question that remains unaddressed is the relative contribution of a single molecular
cascade to the autism and/or intellectual disability phenotypes in FXS. This is clinically
relevant, because there is not yet an approved therapeutic agent that adequately manages
cognitive impairments that occur in FXS. The challenge, some would argue, is the lack
of clear-cut assays that link circuit dysfunction in mouse models (where most of the
basic FXS-related neuroscience is conducted) to dissect autism spectrum disorder-
and intellectual disability-centric phenotypes, which overlap in many cases. Moreover,
because of the recent disappointing outcomes of drug trials for FXS, affected families
are increasingly turning toward readily available agents that have been previously
used to treat other psychiatric ailments. Although the “bird-in-hand” idea has considerable
merit, it becomes critical to understand how these tested medicines work in the context
of FXS. The elegant study by Franklin et al.
- Franklin A.V
- King M.K.
- Palomo V.
- Martinez A.
- McMahon L.L.
- Jope R.S.
Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and
cognition in fragile X mice.
) in this issue of Biological Psychiatry
sheds some light on the aforementioned issues. The authors not only provide additional
evidence that lithium, via glycogen synthase kinase-3 (GSK3), has beneficial effects
in treating FXS symptoms but also identify at least one brain circuit from which the
cognitive defects displayed by FXS model mice might be originating.