Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline

R.L Openshaw,D.M Thomson,J.A Pratt,B.J Morris,J.M Penninger

doi:10.1007/s00213-016-4463-y

Abstract

RationaleMembers of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear.ObjectiveIn the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment.MethodsAttentional function in mice haploinsufficient for Map2k7 (Map2k7+/− mice) was investigated using the five-choice serial reaction time task (5-CSRTT).ResultsOnce stable performance had been achieved, Map2k7+/− mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline—a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia—signs of improvement in attentional performance were detected.ConclusionsOverall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

Highlights

Considerable research efforts have focussed on the role of mitogen-activated protein (MAP) kinase signalling cascades in neuronal function
Throughout training and once stable performance had been attained, Map2k7+/− mice consistently showed a similar level of accuracy as WT mice (Figs. 1a and 2a); they performed marginally better at 94.6 ± 0.9 % accuracy compared to WT littermates at 93.5 ± 0.7 % (F(1, 116) = 3.87; p = 0.052) and made fewer commission errors overall (Map2k7+/− 4.063 ± 0.67; WT 5.33 ± 0.48) (F(1, 116) = 17.24; p = 0.0001) (Fig. 1b)
Data analysed by a two-way repeated measures ANOVA with Tukey’s post hoc and are presented as mean ± standard error of the mean (SEM). **p < 0.01; ***p < 0.001, NWT = 15, NMap2k7+/ − = 16

Summary

Introduction

Considerable research efforts have focussed on the role of mitogen-activated protein (MAP) kinase signalling cascades in neuronal function. Less attention has been directed at understanding the role of the c-Jun N-terminal kinase (JNK) pathway in neuronal function In this pathway, three genes (MAPK8–10) encode isoforms of JNK (JNK1–3), which can be activated by either of the upstream kinases MKK4 or MKK7 (Wang et al 2007; Coffey 2014). Mutations in JNK3 cause severe intellectual disability (Shoichet et al 2006; Kunde et al 2013), whilst sequence variations in the MAP2K7 gene (encoding MKK7) are associated with prefrontal cortex dysfunction and cognitive impairment in schizophrenia (Winchester et al 2012) This is consistent with experimental evidence that JNK1, MKK7 and MAP3K12

Methods

Results

Discussion

Conclusion