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(Li+)ghting the Way for a Treatment for Cognitive Impairments in Fragile X Syndrome

      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” (
      • Krueger D.D.
      • Bear M.F.
      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.
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      Linked Article

      • Glycogen Synthase Kinase-3 Inhibitors Reverse Deficits in Long-term Potentiation and Cognition in Fragile X Mice
        Biological PsychiatryVol. 75Issue 3
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          Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes.
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