Fragile X syndrome (FXS) is an inherited form of intellectual disability caused by the loss of the mRNA-binding fragile X mental retardation protein (FMRP). FXS is characterized by neuronal hyperexcitability and behavioral defects, however the mechanisms underlying these critical dysfunctions remain unclear. Here, using male Fmr1 knockout mouse model of FXS, we identify abnormal extracellular potassium homeostasis, along with impaired potassium channel Kir4.1 expression and function in astrocytes. Further, we reveal that Kir4.1 mRNA is a binding target of FMRP. Finally, we show that the deficit in astroglial Kir4.1 underlies neuronal hyperexcitability and several behavioral defects in Fmr1 knockout mice. Viral delivery of Kir4.1 channels specifically to hippocampal astrocytes from Fmr1 knockout mice indeed rescues normal astrocyte potassium uptake, neuronal excitability, and cognitive and social performance. Our findings uncover an important role for astrocyte dysfunction in the pathophysiology of FXS, and identify Kir4.1 channel as a potential therapeutic target for FXS.

• MeSH
• astrocyty * metabolismus   MeSH
• chování zvířat MeSH
• draslík metabolismus   MeSH
• draslíkové kanály dovnitř usměrňující * metabolismus   genetika   MeSH
• hipokampus metabolismus   MeSH
• kanál KCNJ10 MeSH
• messenger RNA metabolismus   genetika   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• neurony * metabolismus   fyziologie   MeSH
• protein FMRP * metabolismus   genetika   MeSH
• syndrom fragilního X * metabolismus   genetika   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• draslík MeSH
• draslíkové kanály dovnitř usměrňující * MeSH
• Fmr1 protein, mouse MeSH Prohlížeč
• kanál KCNJ10 MeSH
• messenger RNA MeSH
• protein FMRP * MeSH

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-/- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.

• Klíčová slova
• Ames negative, Phenylhydroxamate, acetylated α-tubulin, memory and learning impairments, permeability,
• MeSH
• benzamidy farmakologie   MeSH
• chinoliny farmakologie   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• histondeacetylasa 6 antagonisté a inhibitory   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• kognice účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• paměť účinky léků   MeSH
• posttranslační úpravy proteinů účinky léků   MeSH
• syndrom fragilního X enzymologie   patofyziologie   MeSH
• učení účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• benzamidy MeSH
• chinoliny MeSH
• histondeacetylasa 6 MeSH
• inhibitory histondeacetylas MeSH
• SW-100 MeSH Prohlížeč