title: Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen.
abstract: Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the transcriptional silencing of FMR1 and loss of the mRNA translational repressor protein fragile X mental retardation protein (FMRP). Patients with FXS exhibit changes in neuronal dendritic spine morphology, a pathology associated with altered synaptic function. Studies in the mouse model of fragile X have shown that loss of FMRP causes excessive synaptic protein synthesis, which results in synaptic dysfunction and altered spine morphology. We tested whether the pharmacologic activation of the γ-aminobutyric acid type B (GABA(B)) receptor could correct or reverse these phenotypes in Fmr1-knockout mice. Basal protein synthesis, which is elevated in the hippocampus of Fmr1-knockout mice, was corrected by the in vitro application of the selective GABA(B) receptor agonist STX209 (arbaclofen, R-baclofen). STX209 also reduced to wild-type values the elevated AMPA receptor internalization in Fmr1-knockout cultured neurons, a known functional consequence of increased protein synthesis. Acute administration of STX209 in vivo, at doses that modify behavior, decreased mRNA translation in the cortex of Fmr1-knockout mice. Finally, the chronic administration of STX209 in juvenile mice corrected the increased spine density in Fmr1-knockout mice without affecting spine density in wild-type mice. Thus, activation of the GABA(B) receptor with STX209 corrected synaptic abnormalities considered central to fragile X pathophysiology, a finding that suggests that STX209 may be a potentially effective therapy to treat the core symptoms of FXS.
authors.affiliation: Seaside Therapeutics Inc., Cambridge, MA 02139, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Henderson
authors.forename: Lasani
authors.initials: L
authors.lastname: Wijetunge
authors.forename: Mika Nakamoto
authors.initials: MN
authors.lastname: Kinoshita
authors.forename: Matthew
authors.initials: M
authors.lastname: Shumway
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Hammond
authors.forename: Friso R
authors.initials: FR
authors.lastname: Postma
authors.forename: Christopher
authors.initials: C
authors.lastname: Brynczka
authors.forename: Roger
authors.initials: R
authors.lastname: Rush
authors.forename: Alexia
authors.initials: A
authors.lastname: Thomas
authors.forename: Richard
authors.initials: R
authors.lastname: Paylor
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
authors.forename: Peter W
authors.initials: PW
authors.lastname: Vanderklish
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
authors.forename: Randall L
authors.initials: RL
authors.lastname: Carpenter
authors.forename: Mark F
authors.initials: MF
authors.lastname: Bear
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Healy
mesh_terms: D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D060766:Drinking Water; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D005600:Fragile X Syndrome / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D058786:GABA-B Receptor Agonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011132:Polyribosomes / Q000187:drug effects / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy / Q000473:pathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D001418:Baclofen; D060766:Drinking Water; D051860:Fragile X Messenger Ribonucleoprotein 1; D058786:GABA-B Receptor Agonists; D018091:Receptors, AMPA; D018080:Receptors, GABA-B