title: Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome.
abstract: The behavioral and anatomical deficits seen in fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. Although modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABAB) receptors, which are heterodimeric G-protein-coupled receptors constructed from R1a and R2 or R1b and R2 subunits. Via the activation of Gi/o, they limit cAMP accumulation, diminish neurotransmitter release, and induce neuronal hyperpolarization. Here we reveal that selective deficits in R1a subunit expression are seen in Fmr1 knock-out mice (KO) mice, a widely used animal model of FXS, but the levels of the respective mRNAs were unaffected. Similar trends of R1a expression were seen in a subset of FXS patients. GABABreceptors (GABABRs) exert powerful pre- and postsynaptic inhibitory effects on neurotransmission. R1a-containing GABABRs are believed to mediate presynaptic inhibition in principal neurons. In accordance with this result, deficits in the ability of GABABRs to suppress glutamate release were seen in Fmr1-KO mice. In contrast, the ability of GABABRs to suppress GABA release and induce postsynaptic hyperpolarization was unaffected. Significantly, this deficit contributes to the pathophysiology of FXS as the GABABR agonist (R)-baclofen rescued the imbalances between excitatory and inhibitory neurotransmission evident in Fmr1-KO mice. Collectively, our results provided evidence that selective deficits in the activity of presynaptic GABABRs contribute to the pathophysiology of FXS.
authors.affiliation: From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Ji-Yong
authors.initials: JY
authors.lastname: Kang
authors.affiliation: From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Chadchankar
authors.affiliation: From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Thuy N
authors.initials: TN
authors.lastname: Vien
authors.affiliation: the Lieber Institute for Brain Development and.
authors.forename: Michelle I
authors.initials: MI
authors.lastname: Mighdoll
authors.affiliation: the Lieber Institute for Brain Development and.|Departments of Neurology and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.|Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Waltham, Massachusetts 02451.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mather
authors.affiliation: From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Tarek Z
authors.initials: TZ
authors.lastname: Deeb
authors.affiliation: Innovative Medicines and Early Development, AstraZeneca, Melbourn Science Park, Cambridge Road, Royston Herts SG8 6EE, United Kingdom, and.
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.affiliation: From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.|Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Waltham, Massachusetts 02451.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.|Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Waltham, Massachusetts 02451.
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, Stephen.Moss@Tufts.edu.|Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Waltham, Massachusetts 02451.|the Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D018698:Glutamic Acid; D012333:RNA, Messenger; D018080:Receptors, GABA-B; D012694:Serine; D005680:gamma-Aminobutyric Acid; C497684:Fmr1 protein, mouse
keywords: GABA receptor; fragile X; inhibition mechanism; neurotransmitter receptor; presynaptic; synapse; γ-aminobutyric acid (GABA)