Agmatinase, an inactivator of the putative endogenous antidepressant agmatine, is strongly upregulated in hippocampal interneurons of subjects with mood disorders Hans-Gert Bernstein a, * , Claudia Stich a , Kristin Jäger b , Henrik Dobrowolny a , Martin Wick a , Johann Steiner a , Rüdiger Veh c , Bernhard Bogerts a , Gregor Laube c a Department of Psychiatry, University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany b Institute of Anatomy and Cell Biology, Große Steinstraße 52, D-06108 Halle, Germany c Institute for Integrative Neuroanatomy, Charité, Philippstr. 12, 10115 Berlin, Germany article info Article history: Received 1 April 2011 Received in revised form 28 June 2011 Accepted 12 July 2011 Keywords: Agmatinase Unipolar depression Bipolar depression Hippocampus Immunohistochemistry Morphometry abstract The diamine agmatine may serve as a precursor in polyamine synthesis. In addition, agmatine may also act as a neurotransmitter, binding to imidazoline receptors. Behaviorally, agmatine exerts antidepressant-like effects. The enzyme agmatinase degrades agmatine. The gene coding for human agmatinase is located on chromosome 1p36, a gene locus which has been linked to bipolar disorder and major depression, but the enzyme has not yet been studied in the context of neuropsychiatric diseases. We analyzed agmatinase protein expression in postmortem hippocampi of individuals with affective disorders. Data from eleven patients with mood disorders (unipolar and bipolar depression) and twelve matched control cases were compared by immunocytochemical and morphometrical analysis. Agmatinase protein was detected in a subset of hippocampal interneurons. The protein was localized to perikarya, neurites and putative nerve endings contacting hippocampal pyramidal neurons and dentate gyrus granule cells. The number and the numerical density of agmatinase-immunopositive cell bodies were strongly elevated in depressive patients. In addition, a significantly increased density of agmatinase- immunoreactive punctate profiles was observed in the CA 4 region in unipolar and bipolar depression. The reported increased expression of agmatinase suggests a functional relevance of the enzyme in the pathophysiology of human affective disorders. This article is part of a Special Issue entitled ‘Anxiety and Depression’. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Polyamines serve a plethora of important cellular functions in all cells and tissues including the central nervous system (Bernstein and Müller, 1999). They may be synthesized via two distinct pathways, both leading to the formation of the diamine putrescine (Pegg, 1986; Sastre et al., 1996; Agostinelli et al., 2010). The “classical” pathway involves the enzymes arginase (EC 3.5.3.) and ornithine decarbox- ylase (EC 4.1.1.17; ODC), while the putative alternative pathway is driven by arginine decarboxylase (EC 4.1.1.19) and agmatinase (aka arginine ureohydrolase or agmatine amidinohydrolase; EC 3.5.3.11). In the latter pathway the activity of arginine decarboxylase gener- ates an intermediate product, agmatine (4-aminobutylguanidine), which in a subsequent metabolic step is cleaved into putrescine and urea by the enzyme agmatinase (Gilad et al., 1996; for overviews see Wiesinger, 2001; Agostinelli et al., 2010). In the rat brain, however, agmatine may also be inactivated by a structurally unrelated “agmatinase-like protein” (Mella et al., 2010). During the past decade, agmatine has increasingly been recog- nized as an important neuromodulator, possibly even serving as a neurotransmitter (Reis and Regunathan, 1998) in the brain. It is a clonidine displacing substance, which acts as an endogenous ligand of imidazoline receptors (Reis and Regunathan, 1999; Raasch et al., 2001). Biochemically, it was detected in several brain regions, with Abbreviations: aka, also known as; Agm-GST, GST fusion protein containing amino acids 176e353 from agmatinase sequence; Agm-His, 6His-tagged thio- redoxin fusion protein containing amino acids 176e353 from agmatinase I sequence; ANOVA, analysis of variance (between groups); Arg I-GST, fusion protein containing amino acids 113e323 from arginase I sequence; Arg1-His, 6His-tagged thioredoxin fusion protein containing amino acids 176e353 from Agm sequence; BD, bipolar depression/disorder; CA, cornu ammonis; CAT, cationic amino acid transporter; DSM, Diagnostic and Statistic Manual of Mental Disorders-Revised; IR, immunoreactive; LOD, logarithm (base 10) of odds; NMDA, N-methyl-D-aspartate; PBS, presubiculum; SB, subiculum; SPSS, Statistical Product and Service Solutions; UD, unipolar depression/major depression. * Corresponding author. Tel.: þ49 391 6714249; fax: þ49 391 6715223. E-mail address: hans-gert.bernstein@med.ovgu.de (H.-G. Bernstein). Contents lists available at SciVerse ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.07.012 Neuropharmacology 62 (2012) 237e246