Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein–protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP–channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications.
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This work was supported in part by R35 grant NS111596 to V.A.K. from the National Institute of Neurological Disorders and Stroke (NINDS). The authors apologize to colleagues whose work could not be cited in this Review due to space limitations. Figures 1 and 2 were created with BioRender.com.
The authors declare no competing interests
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Nature Reviews Neuroscience thanks L. Kaczmarek and R. Hagerman, and the other anonymous reviewer(s), for their contribution to the peer review of this work.
A condition in which males have abnormally large testes.
A heterogeneous group of disorders resulting from the dysfunction of ion channels, which can be caused by mutations either in genes encoding channels themselves or in related factors that regulate ion channels.
An abnormal state of a neuron characterized by increased probability of firing action potentials in response to an input.
- Audiogenic seizures
Seizures that are triggered by acoustic stimulation.
- UP states
One of the two preferred subthreshold membrane potentials of a neuron, characterized by a more depolarized state during which it is easier for a neuron to fire action potentials.
- Feedforward inhibition
A ubiquitous unitary motif in the organization of neural circuits in which an excitatory neuron excites an inhibitory interneuron, which then in turn inhibits a downstream excitatory cell (or cells).
The ability of the finger joints to move beyond their normal range of motion.
- Intratelencephalic projecting pyramidal cells
Telencephalic pyramidal cells whose axons project to regions within the telencepalon.
- Critical period
A time period during early postnatal life when the development and maturation of functional properties of the brain is strongly dependent on experiences or environmental influences.
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Deng, PY., Klyachko, V.A. Channelopathies in fragile X syndrome. Nat Rev Neurosci 22, 275–289 (2021). https://doi.org/10.1038/s41583-021-00445-9