Impairment of hippocampal CA1 heterosynaptic transformation and spatial memory by beta-amyloid(25-35).
In Alzheimer's disease, the cholinergic damage (reduced neurotransmission) and cognitive impairment occur long before beta-amyloid (Abeta) plaque formation. It has not been established whether the link between soluble Abeta and cholinergic functions contributes to synaptic dysfunction that underlies the cognitive impairment. Here, we report that Abeta(25-35), an active form of Abeta, inhibited long-term synaptic modification that depends on the associative activation of cholinergic and GABAergic inputs when bilaterally injected intracerebroventricularly (icv; 200 microg/site). The Abeta microinjections did not affect single-pulse-evoked glutamatergic and GABAergic synaptic transmission onto the hippocampal CA1 pyramidal cells, while cholinergic intracellular theta; was dramatically reduced by the Abeta(25-35) injection. Spatial memory of the water maze task was also impaired by the bilateral icv Abeta(25-35) injections, while bilateral microinjections of the same dose of Abeta(35-25) was ineffective in affecting the long-term synaptic modification evoked by associative activation of cholinergic and GABAergic inputs, the cholinergic intracellular theta;, or producing memory impairments. Thus restoring the synaptic plasticity involved in this associative activation of cholinergic and GABAergic inputs may offer an important therapeutic target in the treatment of early Abeta-induced memory decline.
Sun
Miao-Kun
MK
Blanchette Rockefeller Neurosciences Institute, Rockville 20850, USA. mksun@brni-jhu.org
Alkon
Daniel L
DL
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013028:Space Perception / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D016229:Amyloid beta-Peptides; D018679:Cholinergic Agonists; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D005680:gamma-Aminobutyric Acid; D002217:Carbachol