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The Journal of Neuroscience, May 23, 2007, 27(21):5683-5693; doi:10.1523/JNEUROSCI.1732-07.2007

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Cellular/Molecular
Cholinergic Axons Modulate GABAergic Signaling among Hippocampal Interneurons via Postsynaptic 7 Nicotinic Receptors

Nicolas Wanaverbecq,^1,2 Alexey Semyanov,¹ Ivan Pavlov,¹ Matthew C. Walker,¹ and Dimitri M. Kullmann¹

¹Institute of Neurology, University College London, London WC1N 3BG, United Kingdom, and ²Biozentrum, University of Basel, CH-4056 Basel, Switzerland

Correspondence should be addressed to Dimitri M. Kullmann, Institute of Neurology, Queen Square, London WC1N 3BG, UK. Email: d.kullmann{at}ion.ucl.ac.uk

Homopentameric 7 nicotinic receptors have a high affinity for acetylcholine (ACh), are permeable to Ca²⁺ ions, and are abundant in hippocampal interneurons. Although nicotinic agonists evoke inward currents and Ca²⁺ transients in stratum radiatum interneurons, the role of endogenous ACh in modulating synaptic integration by interneurons is incompletely understood. Many cholinergic axonal varicosities do not have postsynaptic specializations, but 7 receptors frequently occur close to synaptic GABA_A receptors. These observations raise the possibility that 7 nicotinic receptors activated by ACh released from cholinergic axons modulate GABAergic transmission in interneurons. We show that agonists of 7 receptors profoundly depress GABAergic IPSCs recorded in stratum radiatum interneurons in the CA1 region of the hippocampus. This depression is accompanied by a small increase in GABA release. 7 nicotinic receptor agonists also depress GABA- or muscimol-evoked currents in interneurons, indicating that the major effect is a postsynaptic modulation of GABA_A receptors. The depression of GABA-evoked currents is abolished by chelating Ca²⁺ in the recorded interneuron and attenuated by inhibitors of PKC. We also show that stimuli designed to release endogenous ACh from cholinergic axons evoke an 7 receptor-dependent heterosynaptic depression of GABAergic IPSCs in interneurons. This heterosynaptic modulation is amplified by blocking cholinesterases. These results reveal a novel mechanism by which cholinergic neurons modulate information processing in the hippocampus.

Key words: nicotinic; GABA_A receptor; interneurons; cholinergic; hippocampus; inhibition

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Received Sept. 19, 2006; accepted April 18, 2007.

Correspondence should be addressed to Dimitri M. Kullmann, Institute of Neurology, Queen Square, London WC1N 3BG, UK. Email: d.kullmann{at}ion.ucl.ac.uk

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