Neuroscience Letters 449 (2009) 220–223 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Muscarinic acetylcholine receptors and voltage-gated calcium channels contribute to bidirectional synaptic plasticity at CA1-subiculum synapses Oded Lipa Shor a,b , Pawel Fidzinski a,b,∗,1 , Joachim Behr a,b,1 a Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany b Johannes Mueller Institute of Physiology, Charité Universitätsmedizin Berlin, Tucholskystr. 2, 10117 Berlin, Germany article info Article history: Received 20 August 2008 Received in revised form 5 November 2008 Accepted 6 November 2008 Keywords: Hippocampus Neuromodulation Long-term potentiation Long-term depression Learning and memory abstract Hippocampal output is mediated via the subiculum, which is the principal target of CA1 pyramidal cells, and which sends projections to a variety of cortical and subcortical regions. Pyramidal cells in the subicu- lum display two different firing modes and are classified as being burst-spiking or regular-spiking. In a previous study, we found that low-frequency stimulation induces an NMDA receptor-dependent long- term depression (LTD) in burst-spiking cells and a metabotropic glutamate receptor-dependent long-term potentiation (LTP) in regular-spiking cells [P. Fidzinski, O. Shor, J. Behr, Target-cell-specific bidirectional synaptic plasticity at hippocampal output synapses, Eur. J. Neurosci., 27 (2008) 1111–1118]. Here, we present evidence that this bidirectional plasticity relies upon the co-activation of muscarinic acetylcholine receptors, as scopolamine blocks synaptic plasticity in both cell types. In addition, we demonstrate that the L-type calcium channel inhibitor nifedipine converts LTD to LTP in burst-spiking cells and LTP to LTD in regular-spiking cells, indicating that the polarity of synaptic plasticity is modulated by voltage-gated calcium channels. Bidirectional synaptic plasticity in subicular cells therefore appears to be governed by a complex signaling system, involving cell-specific recruitment of ligand and voltage-gated ion channels as well as metabotropic receptors. This complex regulation might be necessary for fine-tuning of synaptic efficacy at hippocampal output synapses. © 2008 Elsevier Ireland Ltd. All rights reserved. Hippocampal output is mediated via the subiculum, which is the principal target of CA1 pyramidal cells [1], and which sends pro- jections to a variety of cortical and subcortical regions [38]. The critical role of the subiculum in the encoding and retrieval of mem- ory traces has been demonstrated in both rats [11] and humans [13]. These findings, coupled with the anatomical connections, support the view that the subiculum is a prominent player in hippocampal–cortical information processing. The ability of synapses to undergo activity-dependent changes is regarded as crucial for memory formation [28]. Long-term poten- tiation (LTP) and long-term depression (LTD) of synaptic efficacy have been the subject of investigation in various brain structures [27], including the subiculum [10,24,19,25]. In response to affer- ent stimulation or depolarizing current injections, pyramidal cells in the subiculum and the CA1 display two different firing modes. These modes are classified as burst-spiking (BS) and regular-spiking ∗ Corresponding author at: Max-Delbrück-Centrum/Leibniz Institut für moleku- lare Pharmakologie, Robert-Rössle-Str. 10, 13215 Berlin, Germany. Tel.: +49 30 9406 2966; fax: +49 30 9406 2960. E-mail address: pawel.fidzinski@mdc-berlin.de (P. Fidzinski). 1 These authors contributed equally to this work. (RS), respectively [22,29,40–42,14]. In CA1, the majority of pyra- midal cells displays RS behaviour, whereas in the subiculum both firing modes are found, with an increasing percentage of BS cells towards the distal subiculum [40,20]. We found that low-frequency stimulation (LFS) induces an NMDA receptor (NMDAR)-dependent LTD in subicular BS cells and a metabotropic glutamate receptor (mGluR)-dependent late-onset LTP in subicular RS cells [12]. Both forms of synaptic plasticity require postsynaptic calcium signaling. In the present study, we present evidence that this bidirectional plasticity relies upon the co-activation of muscarinic acetylcholine receptors (mAChR), as scopolamine blocks synaptic plasticity in both cell types. Moreover, nifedipine modulates the direction of synaptic plasticity in each cell type, indicating the involvement of voltage-gated calcium channels (VGCC) in the induction process. Wistar rats (4–6 weeks) of both sexes were decapitated under deep ether anaesthesia and the brains were quickly removed. 400 m thick horizontal slices from the ventral-to-middle part con- taining the hippocampus and the entorhinal cortex were prepared using a vibratome (Campden Instruments, Loughborough, UK). The preparation was performed in ice-cold, saccharose-based artificial cerebrospinal fluid (ACSF) (in mM): NaCl 87, Na 2 PO 4 1.25, NaHCO 3 26, KCl 2.5, CaCl 2 0.5, MgCl 2 7, saccharose 75, and glucose 25 at a pH of 7.4. After preparation, slices were kept under submerged condi- 0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2008.11.012