Theta-frequency synaptic potentiation in CA1 in vitro distinguishes cognitively impaired from unimpaired aged Fischer 344 rats.
Hippocampal-dependent learning and memory deficits have been well documented in aging rodents. The results of several recent studies have suggested that these deficits arise from weakened synaptic plasticity within the hippocampus. In the present study, we examined the relationship between hippocampal long-term potentiation (LTP) in vitro and spatial learning in aged (24-26 months) Fischer 344 rats. We found that LTP induced in the CA1 region using theta-frequency stimulation (5 Hz) is selectively impaired in slices from a subpopulation of aged rats that had shown poor spatial learning in the Morris water maze. LTP at 5 Hz in aged rats that did not show learning deficits was similar to that seen in young (4-6 months) controls. We also found that 5 Hz LTP amplitude strongly correlated with individual learning performance among aged rats. The difference in 5 Hz LTP magnitude among aged rats was not attributable to an altered response to 5 Hz stimulation or to differences in the NMDA receptor-mediated field EPSP. In addition, no performance-related differences in LTP were seen when LTP was induced with 30 or 70 Hz stimulation protocols. Finally, both 5 Hz LTP and spatial learning in learning-impaired rats were enhanced with the selective muscarinic M2 antagonist BIBN-99 (5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one). These findings reinforce the idea that distinct types of hippocampal LTP offer mechanistic insight into age-associated cognitive decline.
Tombaugh
Geoffrey C
GC
Memory Pharmaceuticals Corporation, Montvale, New Jersey 07645, USA. tombaugh@memorypharma.com
Rowe
Wayne B
WB
Chow
Ana R
AR
Michael
Timothy H
TH
Rose
Gregory M
GM
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000503:physiopathology*; D003984:Dibenzazepines / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000503:physiopathology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000187:drug effects; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D013826:Theta Rhythm
D003984:Dibenzazepines; D018727:Muscarinic Antagonists; D011725:Pyridines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; C079888:BIBN 99