title: Neuroligin1 drives synaptic and behavioral maturation through intracellular interactions.
abstract: In vitro studies suggest that the intracellular C terminus of Neuroligin1 (NL1) could play a central role in the maturation of excitatory synapses. However, it is unknown how this activity affects synapses in vivo, and whether it may impact the development of complex behaviors. To determine how NL1 influences the state of glutamatergic synapses in vivo, we compared the synaptic and behavioral phenotypes of mice overexpressing a full-length version of NL1 (NL1FL) with mice overexpressing a version missing part of the intracellular domain (NL1ΔC). We show that overexpression of full-length NL1 yielded an increase in the proportion of synapses with mature characteristics and impaired learning and flexibility. In contrast, the overexpression of NL1ΔC increased the number of excitatory postsynaptic structures and led to enhanced flexibility in mnemonic and social behaviors. Transient overexpression of NL1FL revealed that elevated levels are not necessary to maintain synaptic and behavioral states altered earlier in development. In contrast, overexpression of NL1FL in the fully mature adult was able to impair normal learning behavior after 1 month of expression. These results provide the first evidence that NL1 significantly impacts key developmental processes that permanently shape circuit function and behavior, as well as the function of fully developed neural circuits. Overall, these manipulations of NL1 function illuminate the significance of NL1 intracellular signaling in vivo, and enhance our understanding of the factors that gate the maturation of glutamatergic synapses and complex behavior. This has significant implications for our ability to address disorders such as autism spectrum disorders.
authors.affiliation: Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hoy
authors.forename: Paola A
authors.initials: PA
authors.lastname: Haeger
authors.forename: John R L
authors.initials: JR
authors.lastname: Constable
authors.forename: Renee J
authors.initials: RJ
authors.lastname: Arias
authors.forename: Raluca
authors.initials: R
authors.lastname: McCallum
authors.forename: Michael
authors.initials: M
authors.lastname: Kyweriga
authors.forename: Lawrence
authors.initials: L
authors.lastname: Davis
authors.forename: Eric
authors.initials: E
authors.lastname: Schnell
authors.forename: Michael
authors.initials: M
authors.lastname: Wehr
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
authors.forename: Philip
authors.initials: P
authors.lastname: Washbourne
mesh_terms: D000818:Animals; D001303:Auditory Cortex / Q000254:growth & development / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000502:physiology*; D049229:Dendritic Spines / Q000502:physiology / Q000648:ultrastructure; D004318:Doxycycline / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D049452:Green Fluorescent Proteins; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007859:Learning Disabilities / Q000235:genetics / Q000523:psychology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D021641:Recognition, Psychology; D015290:Second Messenger Systems / Q000502:physiology*; D012919:Social Behavior; D012930:Social Dominance; D013569:Synapses / Q000502:physiology*; D013574:Synaptosomes / Q000502:physiology
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C093438:neuroligin 1; D049452:Green Fluorescent Proteins; D004318:Doxycycline