title: Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission.
abstract: Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1), which is required for production of the Alzheimer's disease (AD)-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC). Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates.
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, St 328A, Boston, Massachusetts, 02111, United States of America.
authors.forename: Kendall R
authors.initials: KR
authors.lastname: Walker
authors.affiliation: AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, 02111, United States of America.
authors.forename: Amit
authors.initials: A
authors.lastname: Modgil
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, St 328A, Boston, Massachusetts, 02111, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Albrecht
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, St 328A, Boston, Massachusetts, 02111, United States of America.
authors.forename: Selene
authors.initials: S
authors.lastname: Lomoio
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts, 02111, United States of America.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Haydon
authors.affiliation: AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, 02111, United States of America.|AstraZeneca Neuroscience Innovative Medicines, Cambridge, Massachusetts, 02421, United States of America.|Department of Neuroscience, Physiology and Pharmacology, University College, London, WC1E 6BT, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: Alzheimer's Disease Research Laboratory, Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, St 328A, Boston, Massachusetts, 02111, United States of America.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Tesco
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000503:physiopathology; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism / Q000502:physiology; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism* / Q000502:physiology; D017353:Gene Deletion; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C407306:GGA adaptor proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse