Trans-generation enrichment of clozapine-responsiveness trait in mice using a subchronic hypo-glutamatergic model of schizophrenia:A preliminary study.
Schizophrenia patients who do not respond to clozapine treatment represent the most debilitating type of schizophrenia with unmet needs for novel interventions. To date there is no validated animal model for clozapine-refractory schizophrenia.



We used poor performance in the social preference (SP) test of C57/BL mice exposed to subchronic phencyclidine (PCP) as a correlate of negative signs of schizophrenia. Subsequently the mice were treated with clozapine and according to their SP they were defined as responding (i.e. clozapine/PCP ratio>1.5 SD) or non-responsive to clozapine. In each generation the responding mice were mated to produce the next generation. Unfortunately, the clozapine- non-responsive mice failed to proliferate and were thus excluded from the analyses. This forward genetic paradigm was used to produce the next generation of clozapine-responding mice. We assessed brain glutamic acid decarboxylase-67 (GAD67) protein levels, as a GABA-ergic marker, in the F2 and F3 generations.



Already in the F1 generation of male mice, but not females, it was possible to discriminate between clozapine-responders and non-responders. The rate of responders within each consecutive generation, increased. The increase was more pronounced in females. Up-regulation of GAD67 levels was detected between F2 and F3 only in male clozapine-responder mice, but not in females.



This preliminary proof-of-concept study succeeded in producing a trans-generation enrichment of clozapine-responsiveness trait in a hypo-glutamatergic animal model of negative signs of schizophrenia. This model may serve as a platform to better characterize the clozapine responsiveness trait and offer a model for clozapine-responsive schizophrenia.
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Geha Mental Health Center, Petah Tikva, Israel.
Amir
A
Krivoy
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Irit
I
Gil-Ad
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel.
Igor
I
Tarasenko
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Geha Mental Health Center, Petah Tikva, Israel.
Abraham
A
Weizman
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: michalt@post.tau.ac.il.
Michal
M
Taler
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D003024:Clozapine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010622:Phencyclidine / Q000008:administration & dosage; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D000068618:Selective Breeding; D012919:Social Behavior
D014150:Antipsychotic Agents; D018698:Glutamic Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010622:Phencyclidine; D003024:Clozapine
Clozapine; GAD67; Phencyclidine; Schizophrenia