Increased GABAB receptor signaling in a rat model for schizophrenia

Martijn M Selten; Francisca Meyer; Wei Ba; Astrid Vallès; Dorien A Maas; Moritz Negwer; Vivian D Eijsink; Ruben W M van Vugt; Josephus A van Hulten; Nick H M van Bakel; Joey Roosen; Robert J van der Linden; Dirk Schubert; Michel M M Verheij; Nael Nadif Kasri; Gerard J M Martens

doi:10.1038/srep34240

Increased GABA_B receptor signaling in a rat model for schizophrenia

Sci Rep. 2016 Sep 30:6:34240. doi: 10.1038/srep34240.

Authors

Martijn M Selten¹, Francisca Meyer², Wei Ba^{1

3}, Astrid Vallès^{2

4}, Dorien A Maas^{1

2}, Moritz Negwer⁵, Vivian D Eijsink², Ruben W M van Vugt², Josephus A van Hulten², Nick H M van Bakel², Joey Roosen², Robert J van der Linden², Dirk Schubert¹, Michel M M Verheij¹, Nael Nadif Kasri^{1

3}, Gerard J M Martens²

Affiliations

¹ Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, the Netherlands.
² Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University, Nijmegen, the Netherlands.
³ Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
⁴ Department of Cognitive Neuroscience, Faculty of Psychology and Neurosciences, Maastricht University, Maastricht, the Netherlands.
⁵ Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.

Abstract

Schizophrenia is a complex disorder that affects cognitive function and has been linked, both in patients and animal models, to dysfunction of the GABAergic system. However, the pathophysiological consequences of this dysfunction are not well understood. Here, we examined the GABAergic system in an animal model displaying schizophrenia-relevant features, the apomorphine-susceptible (APO-SUS) rat and its phenotypic counterpart, the apomorphine-unsusceptible (APO-UNSUS) rat at postnatal day 20-22. We found changes in the expression of the GABA-synthesizing enzyme GAD67 specifically in the prelimbic- but not the infralimbic region of the medial prefrontal cortex (mPFC), indicative of reduced inhibitory function in this region in APO-SUS rats. While we did not observe changes in basal synaptic transmission onto LII/III pyramidal cells in the mPFC of APO-SUS compared to APO-UNSUS rats, we report reduced paired-pulse ratios at longer inter-stimulus intervals. The GABA_B receptor antagonist CGP 55845 abolished this reduction, indicating that the decreased paired-pulse ratio was caused by increased GABA_B signaling. Consistently, we find an increased expression of the GABA_B1 receptor subunit in APO-SUS rats. Our data provide physiological evidence for increased presynaptic GABA_B signaling in the mPFC of APO-SUS rats, further supporting an important role for the GABAergic system in the pathophysiology of schizophrenia.