Beta-amyloid(1-42)-induced cholinergic lesions in rat nucleus basalis bidirectionally modulate serotonergic innervation of the basal forebrain and cerebral cortex.
Ample experimental evidence suggests that beta-amyloid (A beta), 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 A beta-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 A beta(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. A beta infusion into the MBN elicited significant anxiety in the elevated plus maze. A beta 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-HT(1A) receptor binding sites indicated reduced serotonergic activity in the somatosensory cortex. In conclusion, the A beta-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.
Harkany
T
T
Department of Animal Physiology, University of Groningen, Kerklaan 30, NL-9750AA Haren, The Netherlands.
O'Mahony
S
S
Keijser
J
J
Kelly
J P
JP
Kónya
C
C
Borostyánkoi
Z A
ZA
Görcs
T J
TJ
Zarándi
M
M
Penke
B
B
Leonard
B E
BE
Luiten
P G
PG
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000473:pathology; D020532:Basal Nucleus of Meynert / Q000473:pathology*; D002799:Cholinergic Fibers / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D003720:Densitometry; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009416:Nerve Regeneration / Q000502:physiology; D009434:Neural Pathways / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000032:analysis / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D013003:Somatosensory Cortex / Q000378:metabolism / Q000473:pathology*; D014316:Tritium
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; C075222:amyloid beta-protein (1-42); D014316:Tritium; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin