Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity

Christina M Grimm,Birgit Liss,Sonat Aksamaz,Dennis Kätzel,Piotr Sicinski,Jasper Teutsch,Stefanie Schulz

doi:10.1038/s41398-018-0268-6

Abstract

Elevated activity at the output stage of the anterior hippocampus has been described as a physiological endophenotype of schizophrenia, and its development maps onto the transition from the prodromal to the psychotic state. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia could be promising therapies. However, animal models with high construct validity to support such pre-clinical development are scarce. The Cyclin-D2 knockout (CD2-KO) mouse model shows a hippocampal parvalbumin-interneuron dysfunction, and its pattern of hippocampal over-activity shares similarities with that seen in prodromal patients. Conducting a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a rodent correlate of positive symptoms of schizophrenia), that was largely resistant against D1- and D2-dopamine-receptor antagonism, but responsive to the mGluR2/3-agonist LY379268. In the negative symptom domain, CD2-KO mice showed transiently reduced sucrose-preference (anhedonia), but enhanced interaction with novel mice and objects, as well as normal nest building and incentive motivation. Also, unconditioned anxiety, perseveration, and motor-impulsivity were unaltered. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, and also an impairment in working memory, that was resistant against LY379268-treatment. In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.

Highlights

The re-creation of endophenotypes of psychiatric diseases in animal models has been proposed as a promising strategy to meet the current challenge of identifying rodent models with predictive validity for drug discovery[1]
This suggests that Cyclin-D2 knockout (CD2-KO) mice are sensitive to amphetamine as controls; if anything, amphetamine aligns the wildtype with the knockout levels of locomotor activity (Fig. 1f)
We here did a comprehensive behavioural assessment of deficits across the three symptom domains of schizophrenia in the Cyclin-D2-KO mouse model of ventral hippocampal hyperactivity. That this mouse line gains its construct validity as a model of schizophrenia from (1) a hypofunction of parvalbuminpositive interneurons, (2) reduced hippocampal volume, and (3) a lack of adult neurogenesis - three cellular pathologies observed in schizophrenia[2,15,16,20,21,22,37]

Summary

Introduction

The re-creation of endophenotypes of psychiatric diseases in animal models has been proposed as a promising strategy to meet the current challenge of identifying rodent models with predictive validity for drug discovery[1]. Rodent correlates of the positive symptom domain were induced by direct electrical or chemical stimulation of the vHC5–7 Developmental manipulations such as pre-natal methylazoxymethanol acetate (MAM) injections[8,9], which lead to vHC hyperactivity later (and prefrontal aberrations), have been used. It is well established, that such vHC hyperactivity entails a hyper-dopaminergic state of the mesolimbic projection[5,8], and thereby deficits of latent[9,10] and prepulse inhibition[6,7,9], and enhanced novelty- and amphetamine-induced hyperlocomotion[5,7,8]

Methods

Results

Conclusion