PT  - JOURNAL ARTICLE
AU  - Christina M. Grimm
AU  - Sonat Aksamaz
AU  - Stefanie Schulz
AU  - Jasper Teutsch
AU  - Piotr Sicinski
AU  - Birgit Liss
AU  - Dennis Kätzel
TI  - Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity
AID  - 10.1101/301226
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 301226
4099  - http://biorxiv.org/content/early/2018/04/14/301226.short
4100  - http://biorxiv.org/content/early/2018/04/14/301226.full
AB  - Elevated metabolism and neural 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 of this disease. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia may be promising therapeutic strategies. However, animal models with high construct validity to support such pre-clinical development are lacking. We here describe a large-scale phenotyping of the Cyclin-D2 knockout (CD2-KO) mouse model which shows a hippocampal Parvalbumin-interneuron dysfunction and a pattern of hippocampal over-activity similar to that seen in prodromal patients. We found, that CD2-KO mice displayed novelty-induced hyperlocomotion (a correlate in the positive symptom domain), that was largely resistant against D1- and D2-dopamine receptor antagonism, but fully responsive to the mGlu2/3R-agonist LY379268. In the negative symptom domain, CD2-KO mice showed no impairment in social interaction, nest building, or incentive motivation, but transient anhedonia in the sucrose-preference task. Also, unconditioned anxiety, perseveration, and motor impulsivity were normal. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, but also an impairment in working memory, that was resistant against LY379268. 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 cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.