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J Physiol Volume 576, Number 2, 361-377, October 15, 2006 DOI: 10.1113/jphysiol.2006.114587
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MOLECULAR AND GENOMIC

Nicotine-induced enhancement of synaptic plasticity at CA3–CA1 synapses requires GABAergic interneurons in adult anti-NGF mice

Marcelo Rosato-Siri1, Antonino Cattaneo1,2 and Enrico Cherubini1

1 Neuroscience Programme, International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy
2 Lay Line Genomics, Via di Castel Romano 100, 00128 Rome, Italy

The hippocampus, a key structure for learning and memory processes, receives an important cholinergic innervation and is densely packed with a variety of nicotinic acetylcholine receptors (nAChRs) localized on principal cells and interneurons. Activation of these receptors by nicotine or endogenously released acetylcholine enhances activity-dependent synaptic plasticity processes. Deficits in the cholinergic system produce impairment of cognitive functions that are particularly relevant during senescence and in age-related neurodegenerative pathologies. In particular, Alzheimer's disease (AD) is characterized by a selective loss of cholinergic neurons in the basal forebrain and nAChRs in particular regions controlling memory processes such as the cortex and the hippocampus. Field excitatory postsynaptic potentials were recorded in order to examine whether nicotine was able to regulate induction of long-term potentiation at CA3–CA1 synapses in hippocampal slices from adult anti-NGF transgenic mice (AD 11), a comprehensive animal model of AD, in which cholinergic deficits due to nerve growth factor depletion are accompanied by progressive Alzheimer-like neurodegeneration. Both AD 11 and wild-type (WT) mice exhibited short- and long-lasting synaptic plasticity processes that were boosted by nicotine. The effects of nicotine on WT and AD 11 mice were mediated by both {alpha}7- and ß2-containing nAChRs. In the presence of GABAA receptor antagonists, nicotine failed to boost synaptic plasticity in AD 11 but not in WT mice, indicating that in anti-NGF transgenic mice GABAergic interneurons are able to compensate for the deficit in cholinergic modulation of glutamatergic transmission. This compensation may occur at different levels and may involve the reorganization of the GABAergic circuit. However, patch-clamp whole-cell recordings from principal cells failed to reveal any change in spontaneous release of GABA following pressure application of nicotine to nearby GABAergic interneurons. Together, these experiments indicate that in AD 11 mice a rearrangement of the GABAergic circuit can ‘rescue’ nicotine-induced potentiation of synaptic plasticity. This may be relevant for developing proper therapeutic tools useful for the treatment of AD.

(Received 1 June 2006; accepted after revision 20 July 2006; first published online 27 July 2006)
Corresponding author E. Cherubini: Neuroscience Programme, International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy. Email: cher{at}sissa.it






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