In vivo co-ordinated interactions between inhibitory systems to control glutamate-mediated hippocampal excitability M. J. Rodrı ´guez, P. Robledo, 1 C. Andrade, and N. Mahy Unitat de Bioquı ´mica, Institut d’Investigacions Biome `diques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain Abstract We present an overview of the long-term adaptation of hippocampal neurotransmission to cholinergic and GABAergic deafferentation caused by excitotoxic lesion of the medial septum. Two months after septal microinjection of 2.7 nmol a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), a 220% increase of GABA A receptor labelling in the hippo- campal CA3 and the hilus was shown, and also changes in hippocampal neurotransmission characterised by in vivo microdialysis and HPLC. Basal amino acid and purine extra- cellular levels were studied in control and lesioned rats. In vivo effects of 100 mM KCl perfusion and adenosine A 1 receptor blockade with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) on their release were also investigated. In lesioned animals GABA, glutamate and glutamine basal levels were decreased and taurine, adenosine and uric acid levels increased. A similar response to KCl infusion occurred in both groups except for GABA and glutamate, which release decreased in lesioned rats. Only in lesioned rats, DPCPX increased GABA basal level and KCl-induced glutamate release, and decreased glutamate turnover. Our results evidence that an excitotoxic septal lesion leads to increased hippocampal GABA A receptors and decreased glutamate neurotransmis- sion. In this situation, a co-ordinated response of hippocampal retaliatory systems takes place to control neuron excitability. Keywords: adenosine, excitotoxicity, GABA, glutamate, microdialysis, taurine. J. Neurochem. (2005) 95, 651–661. Neurochemical features of normal brain ageing, in particular those associated with memory impairments and neurodegen- erative diseases, have generated intense research activities over the last decades. As a classical model, lesions of the basal forebrain causing disruption of the septohippocampal pathway have consistently mimicked some of these impair- ments in cognitive processing and revealed reductions in cholinergic markers in the hippocampus (Waite et al. 1994; Zapata et al. 2000). However, it appears evident that age- related alterations in brain cholinergic activity cannot fully account for all those cognitive deficits, and that other neurotransmitters are also involved. For instance, a reduction in the number of GABAergic neurons located in the medial septum (MS) and the diagonal band of Brocca (DBB) projecting to the hippocampus also contribute to some of these cognitive impairments (McAlonan et al. 1995; Venero and Hefti 1998). But among all neurotransmitters, glutamate (Glu) is considered of special relevance given its involve- ment in memory-related phenomena, such as long-term potentiation, and its central role in excitotoxicity. The excitotoxic hypothesis of CNS injury is based on an excessive glutamate-mediated excitation that stands out as a critical factor common to a variety of neurological disorders (Obrenovitch and Urenjak 1997; Obrenovitch et al. 2000; Arundine and Tymianski 2004). It is generally accepted that excitotoxic injury to neurons results from excessive inward currents of Ca 2+ and Na + through glutamate-operated ion channels, supplemented by release of Ca 2+ from intracellular stores subsequent to metabotropic Glu receptor activation, Received February 3, 2005; revised manuscript received June 22, 2005; accepted June 24, 2005. Address correspondence and reprint requests to Dr Nicole Mahy, Unitat de Bioquı ´mica, Fac. Medicina, UB, c/ Casanova 143, E-08980 Barcelona, Spain. E-mail: nmahy@ub.edu 1 The present address of P. Robledo is Universitat Pompeu Fabra, Lab- oratori de Neurofarmacologia, Barcelona, Spain. Abbreviations used: AChE, acetylcholinesterase; Ado, adenosine; AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionate; Asp, aspar- tate; AUC, area under the curve; ChAT, choline O-acetyltransferase; DBB, diagonal band of Brocca; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; Gln, glutamine; Glu, glutamate; Gly, glycine; KW, Kruskal–Wallis; MK-801, dizocilpine maleate; MS, medial septum; NGS, normal goat serum; NSE, neuron specific enolase; OPA, O-phthaldialdehyde; PBS, phosphate-buffered saline; QNB, quinuclidinil benzilate; Ser, serine; Tau, taurine. Journal of Neurochemistry , 2005, 95, 651–661 doi:10.1111/j.1471-4159.2005.03394.x Ó 2005 International Society for Neurochemistry, J. Neurochem. (2005) 95, 651–661 651