Assessment of cognitive function in the heterozygous reeler mouse

Abstract

RATIONALE-The heterozygous reeler mouse has been proposed as a genetic mouse model of schizophrenia, based on several neuroanatomical and behavioral similarities between these mice and patients with schizophrenia. However, the effect of reelin haploinsufficiency on one of the cardinal symptoms of schizophrenia, the impairment of prefrontal cortex-dependent cognitive function, has yet to be determined.OBJECTIVE-Here, we investigated multiple aspects of cognitive function in heterozygous reeler mice that are known to be impaired in schizophrenic patients.METHODS-Heterozygous reeler mice were assessed for (1) cognitive flexibility in an instrumental reversal learning task; (2) impulsivity in an inhibitory control task; (3) attentional function in a threechoice serial reaction time task; and (4) working memory in a delayed matching-to-position task.RESULTS-No differences were found between heterozygous reeler mice and wild-type littermate controls in any prefrontal-related cognitive measures. However, heterozygous reeler mice showed deficits in the acquisition of two operant tasks, consistent with a role for reelin in certain forms of learning.CONCLUSIONS-These findings suggest that heterozygous reeler mice may not be an appropriate model for the core prefrontal-dependent cognitive deficits observed in schizophrenia, but may model more general learning deficits that are associated with many psychiatric disorders.

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

“…Hence the potent inhibition of LTP by Aβ 1-42 in an ApoE ε4 background (Trommer et al, 2005) can be explained by Reelin being outcompeted by ApoE ε4 to activate its downstream signaling and antagonizes Aβ. This is in line with the impaired LTP and cognitive performance seen in Reelin heterozygous knock-out mice (Krueger et al, 2006, Qiu et al, 2006, likely representing a consequence of altered NMDA receptor function in these mice (van den Buuse et al, 2012). In agreement, both Reelin heterozygous knock-out (Ohkubo et al, 2003) and ApoE ε4 knock-in mice (Kobayashi et al, 2003, Harris et al, 2004 show increased levels of Tau phosphorylation.…”

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

“…They also fit with in situ observations where neurons exhibit reduced axonal (Del Rio et al, 1997;Borrell et al, 1999) and dendritic branching, as well as stunted dendritic growth and significantly fewer spines in the complete or partial absence of Reelin or its receptors Niu et al, 2004;Borrell et al, 2007;Qiu and Weeber, 2007;Niu et al, 2008). This likely underlies the impaired performance of heterozygous reeler mice in certain learning and memory tasks as compared to wild type controls (Tueting et al, 1999;Krueger et al, 2006;Qiu et al, 2006c;Qiu et al, 2006a;Barr et al, 2007;Qiu and Weeber, 2007). While the total levels of AMPA and NMDA receptors in the hippocampus were comparable between heterozygous reeler and wt littermates (Qiu et al, 2006c;Niu et al, 2008), a significant reduction in synaptic NMDA receptors has been described in the mutants as compared to wt (Niu et al, 2008), pointing again to the critical role of Reelin in glutamate receptor trafficking and composition.…”

Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

“…These results are in partial contrast with previous studies investigating cognitive abilities in rl/+ mice. Specifically, Krueger et al (2006) failed to observe attentional deficits in rl/+ mice in a three-choice serial reaction time task in an operant conditioning chamber. Likewise, Salinger et al (2003) did not observe major differences between in rl/+ and +/+ mice in a thorough test battery addressing social, emotional, locomotor and cognitive performances.…”