Analysis of prepulse inhibition in mouse lines overexpressing 22q11.2 orthologues.
Animal models have been useful in elucidating the genetic basis of the cognitive and behavioural phenotypes associated with the 22q11.2 microdeletions. Loss-of-function models have implicated a number of genes as playing a role in prepulse inhibition (PPI) of the startle response. Here, we report the generation and initial analysis of bacterial artificial chromosome (BAC) transgenic (Tg) mice, overexpressing genes from within the 22q11.2 locus. We used engineered BAC constructs to generate Tg lines and quantitative RT-PCR to assess levels of gene expression in each line. We assessed PPI and open-field activity in mice from two low copy number lines. In Tg-1, a line overexpressing Prodh and Vpreb2, PPI was significantly increased at prepulse levels of 78 dB and 82 dB while no differences were found in activity measures. By contrast, no significant differences were found in PPI testing of the Tg-2 line overexpressing Zdhhc8, Ranbp1, Htf9c, T10, Arvcf and Comt. Taken together with previous loss-of-function reports, these findings suggest that Prodh has a key role in modulating the degree of sensorimotor gating in mice and possibly in humans and provide additional support for an important role of this pathway in modulating behavioural deficits associated with genomic gains or losses at 22q11.2.
Stark
Kimberly L
KL
Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Burt
Rachel A
RA
Gogos
Joseph A
JA
Karayiorgou
Maria
M
D000161:Acoustic Stimulation; D000818:Animals; D001522:Behavior, Animal; D022202:Chromosomes, Artificial, Bacterial; D033481:Chromosomes, Mammalian; D017930:Genes, Reporter; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D054444:Immunoglobulin Light Chains, Surrogate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D010641:Phenotype; D011394:Proline Oxidase / Q000235:genetics; D013216:Reflex, Startle / Q000235:genetics*; D055139:Sensory Gating / Q000235:genetics
D054444:Immunoglobulin Light Chains, Surrogate; C485184:enhanced green fluorescent protein; C515638:pre-B lymphocyte gene 2 protein, mouse; D049452:Green Fluorescent Proteins; D011394:Proline Oxidase