title: Postsynaptic GABAB receptor activity regulates excitatory neuronal architecture and spatial memory.
abstract: Cognitive dysfunction is a common symptom in many neuropsychiatric disorders and directly correlates with poor patient outcomes. The majority of prolonged inhibitory signaling in the brain is mediated via GABAB receptors (GABABRs), but the molecular function of these receptors in cognition is ill defined. To explore the significance of GABABRs in neuronal activity and cognition, we created mice with enhanced postsynaptic GABABR signaling by mutating the serine 783 in receptor R2 subunit (S783A), which decreased GABABR degradation. Enhanced GABABR activity reduced the expression of immediate-early gene-encoded protein Arc/Arg3.1, effectors that are critical for long-lasting memory. Intriguingly, S783A mice exhibited increased numbers of excitatory synapses and surface AMPA receptors, effects that are consistent with decreased Arc/Arg3.1 expression. These deficits in Arc/Arg3.1 and neuronal morphology lead to a deficit in spatial memory consolidation. Collectively our results suggest a novel and unappreciated role for GABABR activity in determining excitatory neuronal architecture and spatial memory via their ability to regulate Arc/Arg3.1.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, United Kingdom, Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, and Innovative Medicines, AstraZeneca, Mereside, Alderley Park, Cheshire SK10 4TG, United Kingdom.
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.forename: Raquel
authors.initials: R
authors.lastname: Revilla-Sanchez
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Quadros
authors.forename: Qiudong
authors.initials: Q
authors.lastname: Deng
authors.forename: Tarek Z
authors.initials: TZ
authors.lastname: Deeb
authors.forename: Michael
authors.initials: M
authors.lastname: Lumb
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.forename: Philip G
authors.initials: PG
authors.lastname: Haydon
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D057567:Memory, Long-Term / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D018080:Receptors, GABA-B / Q000235:genetics / Q000502:physiology*; D013037:Spatial Behavior / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D018080:Receptors, GABA-B; C092069:activity regulated cytoskeletal-associated protein