Editing Fragile X syndrome (section)

== Pathophysiology ==
FMRP is found throughout the body, but in highest concentrations within the brain and testes.<ref name=McLennan/><ref name=Santoro/> It appears to be primarily responsible for selectively binding to around 4% of [[mRNA]] in mammalian brains and transporting it out of the cell nucleus and to the [[synapses]] of [[neurons]]. Most of these mRNA targets have been found to be located in the [[dendrites]] of neurons, and brain tissue from humans with FXS and mouse models shows abnormal [[dendritic spines]], which are required to increase contact with other neurons. The subsequent abnormalities in the formation and function of synapses and development of neural circuits result in impaired [[neuroplasticity]], an integral part of memory and learning.<ref name=McLennan/><ref name=Santoro/><ref>{{cite journal | vauthors = Bassell GJ, Warren ST | title = Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function | journal = Neuron | volume = 60 | issue = 2 | pages = 201–214 | date = October 2008 | pmid = 18957214 | pmc = 3691995 | doi = 10.1016/j.neuron.2008.10.004 }}</ref> [[Connectome]] changes have long been suspected to be involved in the sensory pathophysiology<ref>{{cite journal | vauthors = Bureau I, Shepherd GM, Svoboda K | title = Circuit and plasticity defects in the developing somatosensory cortex of FMR1 knock-out mice | journal = The Journal of Neuroscience | volume = 28 | issue = 20 | pages = 5178–5188 | date = May 2008 | pmid = 18480274 | pmc = 2696604 | doi = 10.1523/JNEUROSCI.1076-08.2008 | author3-link = Karel Svoboda (scientist) }}</ref> and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity.<ref>{{cite journal | vauthors = Haberl MG, Zerbi V, Veltien A, Ginger M, Heerschap A, Frick A | title = Structural-functional connectivity deficits of neocortical circuits in the Fmr1 (-/y) mouse model of autism | journal = Science Advances | volume = 1 | issue = 10 | pages = e1500775 | date = November 2015 | pmid = 26702437 | pmc = 4681325 | doi = 10.1126/sciadv.1500775 | bibcode = 2015SciA....1E0775H }}</ref>

In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The [[Metabotropic glutamate receptor#Group I|group 1 metabotropic glutamate receptor]] (mGluR) pathway, which includes [[Metabotropic glutamate receptor 1|mGluR1]] and [[Metabotropic glutamate receptor 5|mGluR5]], is involved in mGluR-dependent [[long term depression]] (LTD) and [[long term potentiation]] (LTP), both of which are important mechanisms in learning.<ref name=McLennan/><ref name=Santoro/> The lack of FMRP, which represses mRNA production and thereby protein synthesis, leads to exaggerated LTD. FMRP also appears to affect [[dopamine]] pathways in the prefrontal cortex which is believed to result in the attention deficit, hyperactivity and impulse control problems associated with FXS.<ref name=McLennan/><ref name=Santoro/><ref name=Tranfaglia/> The downregulation of [[GABA]] pathways, which serve an inhibitory function and are involved in learning and memory, may be a factor in the anxiety symptoms which are commonly seen in FXS.{{citation needed|date=August 2021}}

Research in a mouse model of FSX shows that cortical neurons receive reduced sensory information (hyposensitivity), contrary to the common assumption that these neurons are hypersensitive, accompanied by enhanced contextual information, accumulated from previous experiences. Therefore, these results suggest that the hypersensitive phenotype of affected individuals might arise from mismatched contextual input onto these neurons.<ref>{{cite journal |vauthors=Mitchell DE, Miranda-Rottmann S, Blanchard MG, Araya R |date=January 2023 |title=Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome |journal=PNAS |volume=120 |issue=2 |pages=e2208963120 |doi=10.1073/pnas.2208963120|pmid=36595706 |pmc=9926222 |bibcode=2023PNAS..12008963M }}</ref>