title: Brain-specific knockin of the pathogenic Tubb5 E401K allele causes defects in motor coordination and prepulse inhibition.
abstract: The generation, migration, and differentiation of neurons requires the functional integrity of the microtubule cytoskeleton. Mutations in the tubulin gene family are known to cause various neurological diseases including lissencephaly, ocular motor disorders, polymicrogyria and amyotrophic lateral sclerosis. We have previously reported that mutations in TUBB5 cause microcephaly that is accompanied by severe intellectual impairment and motor delay. Here we present the characterization of a Tubb5 mouse model that allows for the conditional expression of the pathogenic E401K mutation. Homozygous knockin animals exhibit a severe reduction in brain size and in body weight. These animals do not show any significant impairment in general activity, anxiety, or in the acoustic startle response, however, present with notable defects in motor coordination. When assessed on the static rod apparatus mice took longer to orient and often lost their balance completely. Interestingly, mutant animals also showed defects in prepulse inhibition, a phenotype associated with sensorimotor gating and considered an endophenotype for schizophrenia. This study provides insight into the behavioral consequences of tubulin gene mutations.
authors.affiliation: IMP, Research Institute of Molecular Pathology, Vienna 1030, Austria. Electronic address: mbreuss@ucsd.edu.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Breuss
authors.affiliation: IMP, Research Institute of Molecular Pathology, Vienna 1030, Austria.
authors.forename: Andi H
authors.initials: AH
authors.lastname: Hansen
authors.affiliation: IMP, Research Institute of Molecular Pathology, Vienna 1030, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Landler
authors.affiliation: IMP, Research Institute of Molecular Pathology, Vienna 1030, Austria. Electronic address: david.keays@imp.ac.at.
authors.forename: David A
authors.initials: DA
authors.lastname: Keays
mesh_terms: D000483:Alleles; D000818:Animals; D001007:Anxiety / Q000235:genetics; D001522:Behavior, Animal; D001835:Body Weight; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006720:Homozygote; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity; D065808:Prepulse Inhibition; D045442:Rotarod Performance Test; D014404:Tubulin / Q000235:genetics* / Q000502:physiology*
chemical_list: C000598026:TUBB5 protein, mouse; D014404:Tubulin
keywords: Malformations of cortical development; Microcephaly; Motor defects; Prepulse inhibition; Tubb5; Tubulinopathies