Brain specific knockin of the pathogenic Tubb5 E401K allele causes defects in motor coordination and prepulse inhibition Journal Article

Author(s): Breuss, Martin W; Hansen, Andi H; Landler, Lukas; Keays, David A
Article Title: Brain specific knockin of the pathogenic Tubb5 E401K allele causes defects in motor coordination and prepulse inhibition
Affiliation IST Austria
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.
Keywords: microcephaly; Tubb5; Tubulinopathies; Malformations of cortical development; Motor defects; Prepulse inhibition
Journal Title: Behavioural Brain Research
Volume: 323
ISSN: 1872-7549
Publisher: Elsevier  
Date Published: 2017-04-14
Start Page: 47
End Page: 55
Copyright Statement: CC BY-NC-ND 4.0
DOI: 10.1016/j.bbr.2017.01.029
Notes: We wish to acknowledge the IMP-IMBA transgenic services and the animal attendants for their assistance. MRI acquisition was performed by the Preclinical Imaging Facility of the Campus Science Support Facilities GmbH (CSF). We want to further thankanja Fritz and Marion C. Salzer for excellent technical assistance with mouse colony maintenance and experiments. We are indebted to Boehringer Ingelheim and the Austrian Science Fund (FWF) for funding this research [I914, P21092].
Open access: yes (OA journal)