The reelin receptors VLDLR and ApoER2 regulate sensorimotor gating in mice.
Postmortem brain loss of reelin is noted in schizophrenia patients. Accordingly, heterozygous reeler mutant mice have been proposed as a putative model of this disorder. Little is known, however, about the involvement of the two receptors for reelin, Very-Low-Density Lipoprotein Receptor (VLDLR) and Apolipoprotein E Receptor 2 (ApoER2), on pre-cognitive processes of relevance to deficits seen in schizophrenia. Thus, we evaluated sensorimotor gating in mutant mice heterozygous or homozygous for the two reelin receptors. Mutant mice lacking one of these reelin receptors were tested for prepulse inhibition (PPI) of the acoustic startle reflex prior to and following puberty, and on a crossmodal PPI task, involving the presentation of acoustic and tactile stimuli. Furthermore, because schizophrenia patients show increased sensitivity to N-methyl-d-aspartate (NMDA) receptor blockade, we assessed the sensitivity of these mice to the PPI-disruptive effects of the NMDA receptor antagonist phencyclidine. The results demonstrated that acoustic PPI did not differ between mutant and wildtype mice. However, VLDLR homozygous mice displayed significant deficits in crossmodal PPI, while ApoER2 heterozygous and homozygous mice displayed significantly increased crossmodal PPI. Both ApoER2 and VLDLR heterozygous and homozygous mice exhibited greater sensitivity to the PPI-disruptive effects of phencyclidine than wildtype mice. These results indicate that partial or complete loss of either one of the reelin receptors results in a complex pattern of alterations in PPI function that includes alterations in crossmodal, but not acoustic, PPI and increased sensitivity to NMDA receptor blockade. Thus, reelin receptor function appears to be critically involved in crossmodal PPI and the modulation of the PPI response by NMDA receptors. These findings have relevance to a range of neuropsychiatric disorders that involve sensorimotor gating deficits, including schizophrenia.
Barr
Alasdair M
AM
Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada.
Fish
Kenneth N
KN
Markou
Athina
A
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D053329:Apolipoprotein E2 / Q000172:deficiency / Q000502:physiology*; D001522:Behavior, Animal; D004307:Dose-Response Relationship, Radiation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010622:Phencyclidine / Q000494:pharmacology; D010812:Physical Stimulation / Q000379:methods; D011973:Receptors, LDL / Q000172:deficiency / Q000502:physiology*; D000091042:Reelin Protein; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D053329:Apolipoprotein E2; D018691:Excitatory Amino Acid Antagonists; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C000717128:Reln protein, mouse; D010622:Phencyclidine