Antisense knockdown of the rat α7 nicotinic acetylcholine receptor produces spatial memory impairment

Selective and brain penetrating pharmacological antagonists for use in clarifying a role of alpha 7 nicotinic acetylcholine receptors (nAChR) in behavioral paradigms are presently unavailable. Studies in alpha 7 knock-out mice (KO) have not revealed convincing changes in behavioral phenotype, in particular measures of cognition that include contextual fear conditioning and spatial memory, which may be due to compensatory developmental changes. Therefore, an antisense oligonucleotide (aON) targeted toward the 3'- and 5'-UTR coding regions of the rat alpha 7 nicotinic acetylcholine receptor was used. Following central injection of aON into the lateral ventricle of Long Evans rats for 6 days, treated rats exhibited a significant 42% and 25% decrease in alpha 7 nAChR densities in hippocampus and cortex, respectively, as measured by [H-3]-methyllycaconitine (MLA) binding. There was no change in alpha 4 beta 2 densities measured by [H-3]-cytisine binding. Acquisition of Morris Water Maze (MWM) performance, a measure of spatial memory, was impaired in aON-treated rats. In addition, a reduction in target platform crossings during a subsequent probe-trial was observed. These data demonstrate the ability of this aON to reduce hippocampal and cortical alpha 7 nicotinic receptor densities associated with impaired MWM performance and support the specific involvement of the alpha 7 nAChR in spatial learning and memory, a phenotype not affected in alpha 7 KO mice. (c) 2006 Elsevier Ireland Ltd. All rights reserved.