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Increased GABAB receptor signaling in a rat model for schizophrenia

Selten, M., Meyer, F., Ba, W., Valles, A., Maas, D., Negwer, M., Eijsink, V. D., van Vugt, R. W. M., van Hulten, J. A., van Bakel, N. H. M., Roosen, J., van der Linden, R., Schubert, D., Verheij, M. M. M., Kasri, N. N., & Martens, G. J. M. (2016). Increased GABAB receptor signaling in a rat model for schizophrenia. Scientific Reports, 6: 34240. doi:10.1038/srep34240.
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 GABAB signaling in the mPFC of APO-SUS rats, further supporting an important role for the GABAergic system in the pathophysiology of schizophrenia.
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