Loss of high-affinity nicotinic receptors increases the vulnerability to excitotoxic lesion and decreases the positive effects of an enriched environment.
Pharmacological activation of nicotinic acetylcholine receptors (nAChRs) exerts neuroprotective effects in cultured neurons and the intact animal. Much less is known about a physiological protective role of nAChRs. To understand whether endogenous activation of beta2* nAChRs contributes to the maintenance of the functional and morphological integrity of neural tissue, adult beta2-/- mice were subjected to in vivo challenges that cause neurodegeneration and cognitive impairment (intrahippocampal injection of the excitotoxin quinolinic acid), or neuroprotection and cognitive potentiation (2-month exposure to an enriched environment). The excitotoxic insult caused an increased deficit in the Morris water maze learning curve and increased loss of hippocampal pyramidal cells in beta2-/- mice. Exposure to an enriched environment improved performance in contextual and cued fear conditioning and object recognition tests in beta2+/+, whereas the improvement was absent in beta2-/- mice. In addition, beta2+/+, but not beta2-/-, mice exposed to an enriched environment showed a significant hypertrophy of the CA1/3 regions. Thus, lack of beta2* nAChRs increased susceptibility to an excitotoxic insult and diminished the positive effects of an enriched environment. These results may be relevant to understanding the pathophysiological consequences of the marked decrease in nAChRs that occurs in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
Zanardi
Alessio
A
Department of Biomedical Sciences, Section of Physiology, University of Modena and Reggio Emilia, via Campi 287, 41100 Modena, Italy.
Ferrari
Rosaria
R
Leo
Giuseppina
G
Maskos
Uwe
U
Changeux
Jean-Pierre
JP
Zoli
Michele
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D004779:Environment Design; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009498:Neurotoxins / Q000008:administration & dosage* / Q000633:toxicity; D011485:Protein Binding / Q000235:genetics; D017378:Quinolinic Acid / Q000008:administration & dosage* / Q000633:toxicity; D011978:Receptors, Nicotinic / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D009498:Neurotoxins; D017378:Quinolinic Acid; D011978:Receptors, Nicotinic