β-Amyloid(1-42)-Induced Cholinergic Lesions in Rat Nucleus Basalis Bidirectionally Modulate Serotonergic Innervation of the Basal Forebrain and Cerebral Cortex

• Main Authors: Tibor Harkany, Sheila O'Mahony, Jan Keijser, John P. Kelly, Csaba Kónya, Zsolt A. Borostyánkői, Tamás J. Görcs, Márta Zarándi, Botond Penke, Brian E. Leonard, Paul G.M. Luiten
• Format: Article
• Language: English
• Published: Elsevier 2001-08-01
• Series: Neurobiology of Disease
• Subjects: β-Amyloid; anxiety; magnocellular nucleus basalis; serotonin; sprouting
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996101903985

Ample experimental evidence suggests that β-amyloid (Aβ), when injected into the rat magnocellular nucleus basalis (MBN), impels excitotoxic injury of cholinergic projection neurons. Whereas learning and memory dysfunction is a hallmark of Aβ-induced cholinergic deficits, anxiety, or hypoactivity under novel conditions cannot be attributed to the loss of cholinergic MBN neurons. As mood-related behavioral parameters are primarily influenced by the central serotonergic system, in the present study we investigated whether Aβ(1-42) toxicity in the rat MBN leads to an altered serotonergic innervation pattern in the rat basal forebrain and cerebral cortex 7 days postsurgery. Aβ infusion into the MBN elicited significant anxiety in the elevated plus maze. Aβ toxicity on cholinergic MBN neurons, expressed as the loss of acetylcholinesterase-positive cortical projections, was accompanied by sprouting of serotonergic projection fibers in the MBN. In contrast, the loss of serotonin-positive fiber projections, decreased concentrations of both serotonin and 5-hydroxyindoleacetic acid, and decline of cortical 5-HT1A receptor binding sites indicated reduced serotonergic activity in the somatosensory cortex. In conclusion, the Aβ-induced primary cholinergic deficit in the MBN and subsequent cortical cholinergic denervation bidirectionally modulate serotonergic parameters in the rat basal forebrain and cerebral cortex. We assume that enhanced serotonin immunoreactivity in the damaged MBN indicates intrinsic processes facilitating neuronal recovery and cellular repair mechanisms, while diminished cortical serotonergic activity correlates with the loss of the subcortical cholinergic input, thereby maintaining the balance of neurotransmitter concentrations in the cerebral cortex.