title: Vertebrate intersectin1 is repurposed to facilitate cortical midline connectivity and higher order cognition.
abstract: Invertebrate studies have highlighted a role for EH and SH3 domain Intersectin (Itsn) proteins in synaptic vesicle recycling and morphology. Mammals have two Itsn genes (Itsn1 and Itsn2), both of which can undergo alternative splicing to include DBL/PH and C2 domains not present in invertebrate Itsn proteins. To probe for specific and redundant functions of vertebrate Itsn genes, we generated Itsn1, Itsn2, and double mutant mice. While invertebrate mutants showed severe synaptic abnormalities, basal synaptic transmission and plasticity were unaffected at Schaffer CA1 synapses in mutant mice. Surprisingly, intercortical tracts-corpus callosum, ventral hippocampal, and anterior commissures-failed to cross the midline in mice lacking Itsn1, but not Itsn2. In contrast, tracts extending within hemispheres and those that decussate to more caudal brain segments appeared normal. Itsn1 mutant mice showed severe deficits in Morris water maze and contextual fear memory tasks, whereas mice lacking Itsn2 showed normal learning and memory. Thus, coincident with the acquisition of additional signaling domains, vertebrate Itsn1 has been functionally repurposed to also facilitate interhemispheric connectivity essential for high order cognitive functions.
authors: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors: Ameet S
authors: AS
authors: Sengar
authors: Jacob
authors: J
authors: Ellegood
authors: Adelaide P
authors: AP
authors: Yiu
authors: Hua
authors: H
authors: Wang
authors: Wei
authors: W
authors: Wang
authors: Subhash C
authors: SC
authors: Juneja
authors: Jason P
authors: JP
authors: Lerch
authors: Sheena A
authors: SA
authors: Josselyn
authors: R Mark
authors: RM
authors: Henkelman
authors: Michael W
authors: MW
authors: Salter
authors: Sean E
authors: SE
authors: Egan
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000166:cytology* / Q000254:growth & development*; D003071:Cognition / Q000502:physiology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003337:Corpus Callosum / Q000502:physiology*; D003463:Cues; D056324:Diffusion Tensor Imaging; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear; D007839:Functional Laterality / Q000235:genetics*; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D021621:Imaging, Three-Dimensional; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000235:genetics; D008279:Magnetic Resonance Imaging; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009412:Nerve Fibers / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D014714:Vertebrates / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018691:Excitatory Amino Acid Antagonists; C509777:Itsn2 protein, mouse; C115919:intersectin 1; D015763:2-Amino-5-phosphonovalerate