Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice.
Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology. The presence of the epsilon4 allele of apolipoprotein E was recently implicated as a major risk factor in both familial and sporadic Alzheimer's disease. The present study examined the integrity of cholinergic and non-cholinergic systems in apolipoprotein E-deficient, memory-impaired mice. Choline acetyltransferase activity, hippocampal acetylcholine release, nicotinic and muscarinic (M1 and M2) receptor binding sites and acetylcholinesterase cell or terminal density showed no signs of alteration in either three-month or 9.5-month-old apolipoprotein E-deficient mice compared to controls. In contrast, long-term potentiation was found to be markedly reduced in these mice, but increases in the strength of stimulation induced the same level of long-term potentiation as that observed in controls. These alterations did not appear to be the consequence of modifications in the binding properties of glutamatergic receptors (N-methyl-D-aspartate and [RS]-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) but from defective regulation of the (RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid receptor by phospholipase A2 activity. These results support the notion that apolipoprotein E plays a fundamental role in neuronal plasticity, which could in turn affect cognitive performance through imbalances in extra- and intracellular lipid homeostasis.
Krzywkowski
P
P
Neuroscience Division, Douglas Hospital Research Center, Verdun, Québec, Canada.
Ghribi
O
O
Gagné
J
J
Chabot
C
C
Kar
S
S
Rochford
J
J
Massicotte
G
G
Poirier
J
J
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001345:Autoradiography; D001921:Brain / Q000201:enzymology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D018698:Glutamic Acid / Q000502:physiology; D006651:Histocytochemistry; D017774:Long-Term Potentiation / Q000502:physiology*; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010275:Parasympathetic Nervous System / Q000502:physiology*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects
D001057:Apolipoproteins E; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D018698:Glutamic Acid; D002795:Choline O-Acetyltransferase; D010741:Phospholipases A; D054467:Phospholipases A2; D000110:Acetylcholinesterase; D000109:Acetylcholine