Neuropharmacology and Analgesia Repeated citalopram administration counteracts kainic acid-induced spreading of PSA-NCAM-immunoreactive cells and loss of reelin in the adult mouse hippocampus Külli Jaako ⁎, Anu Aonurm-Helm, Anti Kalda, Kaili Anier, Tamara Zharkovsky, Dmitri Shastin, Alexander Zharkovsky Department of Pharmacology, Centre of Excellence for Translational Medicine, University of Tartu, 19 Ravila St, 50411 Tartu, Estonia abstract article info Article history: Received 28 December 2010 Received in revised form 12 April 2011 Accepted 3 May 2011 Available online 11 May 2011 Keywords: Kainic acid Epilepsy Brain plasticity PSA-NCAM Reelin Citalopram Systemic or intracerebral administration of kainic acid in rodents induces neuronal death followed by a cascade of neuroplastic changes in the hippocampus. Kainic acid-induced neuroplasticity is evidenced by alterations in hippocampal neurogenesis, dispersion of the granule cell layer and re-organisation of mossy fibres. Similar abnormalities are observed in patients with temporal lobe epilepsy and, therefore, kainic acid- induced hippocampal neuroplasticity might mimic pathological mechanisms leading to the formation of ‘epileptic brain’ in patients with temporal lobe epilepsy. Previous studies have demonstrated that selective serotonin re-uptake inhibitor antidepressants might reduce the severity of seizures in epileptic patients and reduce neuronal death in laboratory animal models of kainic acid-induced neurotoxicity. In the present study, we investigated whether kainic acid-induced neuroplasticity in mice is modulated by the repeated administration of citalopram, a selective serotonin reuptake inhibitor. We found that at the histopathological level, repeated citalopram treatment counteracted the kainic acid-induced neuronal loss and dispersion of young granule neurons expressing the polysialylated neural cell adhesion molecule within the granule cell layer of the hippocampus. Citalopram also counteracted the downregulation of reelin on both mRNA and protein levels induced by kainic acid administration. Our findings indicate that repeated administration of citalopram is able to prevent kainic acid-induced abnormal brain plasticity and thereby prevent the formation of an epileptic phenotype. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The systemic or local administration of kainic acid induces widespread neurodegeneration in the brain, the most intense being in the hippocampus, enthorinal cortex and amygdala (Du et al., 1995; Nadler, 1981; Sperk et al., 1985; Tuunanen et al., 1999). In hippocampus, kainic acid-induced neuronal death initiates a cascade of long-lasting neuroplastic changes, like increased proliferative activity, granule cell dispersion in the granule cell layer and re-organisation of mossy fibres (Gray and Sundstrom, 1998; Jessberger et al., 2005; Sutula et al., 1989). It has been shown that seizure activity induces the generation of new cells in the hippocampus where the number of new neurons increases several fold (Nakagawa et al., 2000; Parent et al., 1997). Newly generated cells express the proteins associated with brain plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which is responsible for cell migration, synaptogenesis, axonal growth and branching (Bruses and Rutishauser, 2001; Doherty and Walsh, 1996; Kiss et al., 2001; Rougon, 1993). It has been proposed that the increased neurogenesis could lead to a higher capacity of migration to ectopic sites within the dentate gyrus, which in turn could lead to an increased risk of the establishment of aberrant synaptic contacts and the formation of aberrant neural networks, eventually affecting hippocampal functioning (Jessberger et al., 2005; Sato et al., 2003; Scharfman et al., 2000, 2002). Dispersion of the granule cell layer has also been associated with the loss of molecules responsible for cellular guidance in the brain. The extracellular matrix protein reelin has been suggested as being involved in the development of granule cell dispersion, since the reelin-deficient reeler mouse (Borrell et al., 1999; D'Arcangelo et al., 1995) shows a similar granule cell migration defect (Frotscher et al., 2003; Rakic and Caviness, 1995). In fact, a reelin deficiency was found in the resected hippocampi from temporal lobe epilepsy patients (Haas et al., 2002) as well as in animal models of epilepsy (Heinrich et al., 2006). Selective serotonin reuptake inhibitors, including citalopram, are widely used antidepressant drugs which have also been proposed as a treatment option in epilepsy. Indeed, antidepressants have been demonstrated to reduce seizure activity and duration in animal models of epilepsy as well as in epileptic patients (Borowicz et al., 2006; Favale et al., 2003; Pisani et al., 1999). The mechanism through which antidepressants could alter neuronal excitability and modify the seizure threshold remains largely unknown. It has been proposed European Journal of Pharmacology 666 (2011) 61–71 ⁎ Corresponding author at: Department of Pharmacology, University of Tartu, 50411, 19 Ravila St, Tartu, Estonia. Tel.: + 372 7374 354, + 372 52 42 425; fax: + 372 7374 352. E-mail address: kulli.jaako@ut.ee (K. Jaako). 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.05.008 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar