NEUROCHEMICAL CHARACTERIZATION OF CELLS EXPRESSING THE NOVEL ANALGESIC AND ANTIDEPRESSANT DRUG TARGET SOMATOSTATIN RECEPTOR
01/29/2020
Angela Kecskes1,+1, Krisztina Pohoczky1, 2,+1, Miklos Kecskes3,+1, Zoltan Varga4, Viktoria Kormos1, Nora Henn-Mike3, Eva Szoke1, Attila Gyenesei5, Istvan M Abraham6, Csaba Varga3, Peter Ferdinandy4, Balazs Gaszner7, Zsuzsanna Helyes1
1 Department of Pharmacology and Pharmacotherapy, Medical School & Szentagothai Research Centre, Molecular Pharmacology Research Group, University of Pécs, H-7624, Pécs, Hungary.
2 Department of Pharmacology, Faculty of Pharmacy, University of Pécs, H-7624, Pécs, Hungary.
3 Institute of Physiology, Medical School & Szentagothai Research Centre, Entorhino-hippocampal Neuronal Network Research Group, University of Pécs, H-7624, Pécs, Hungary.
4 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, H-1089, Budapest, Hungary.
5 Szentagothai Research Centre, Bioinformatics Research Group, University of Pécs, H-7624, Pécs, Hungary.
6 Institute of Physiology, Medical School & Szentagothai Research Centre, Molecular Neuroendocrinology Research Group, University of Pécs, H-7624, Pécs, Hungary.
7 Department of Anatomy, Medical School & Szentagothai Research Centre, 8Research Group for Mood Disorders, University of Pécs, H-7624, Pécs, Hungary.
8 Angela Kecskes, Krisztina Pohoczky and Miklos Kecskes contributed equally to this work.
9 Shared corresponding authors: Zsuzsanna Helyes and Balazs Gaszner
Somatostatin is an inhibitory peptide also known as an important pain and mood regulator. Its inhibitory G-protein coupled receptor subtype 4 (sst4) mediates analgesic, anti-inflammatory and antidepressant effects without endocrine actions, but the mechanism of action is poorly understood. It has recently been suggested to be a promising novel drug target for chronic neuropathic pain and depression as comorbidities. However, its distribution in the central nervous system is weakly investigated due to the lack of specific antibody. Therefore, our goals were (i) to elucidate the expression pattern of Sstr4/SSTR4 mRNA in the mouse brain; and characterize (ii) neurochemically and (iii) electrophysiologically the Sstr4+ neuronal populations. We found intense or moderate Sstr4 mRNA expression in pain and mood regulation-related mouse brain regions, including prefrontal and primary somatosensory cortices, amygdala, hippocampus and habenula using the ultrasensitive fluorescent RNAscope in situ hybridization that clearly supports beta-galactosidase immunohistochemistry results in Sstr4lacZ/lacZ reporter mice. Sstr4 is predominantly localized in glutamatergic excitatory neurons, but also in GABAergic inhibitory interneurons and cholinergic neurons in few regions. Furthermore, we provided evidence that sst4 is functionally active in layer V pyramidal neurons of somatosensory cortex. The sst4 agonist, J-2156 significantly decreased the firing frequency of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K+ current (M-current). These are the first data for the expression pattern of sst4 in pain- and mood regulating neurons and its inhibitory function in neocortical glutamatergic cells, which supports the importance of sst4 as a novel drug target.