The Journal of Neurophysiology Vol. 87 No. 5 May 2002, pp. 2441-2449
Copyright ©2002 by the American Physiological Society

Impairment of Hippocampal CA1 Heterosynaptic Transformation and Spatial Memory by -Amyloid_25-35

Blanchette Rockefeller Neurosciences Institute, Rockville 20850; and Laboratory of Adaptive Systems, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Sun, Miao-Kun and Daniel L. Alkon. Impairment of Hippocampal CA1 Heterosynaptic Transformation and Spatial Memory by -Amyloid_25-35. J. Neurophysiol. 87: 2441-2449, 2002. In Alzheimer's disease, the cholinergic damage (reduced neurotransmission) and cognitive impairment occur long before -amyloid (A) plaque formation. It has not been established whether the link between soluble A and cholinergic functions contributes to synaptic dysfunction that underlies the cognitive impairment. Here, we report that A_25-35, an active form of A, inhibited long-term synaptic modification that depends on the associative activation of cholinergic and GABAergic inputs when bilaterally injected intracerebroventricularly (icv; 200 µg/site). The A microinjections did not affect single-pulse-evoked glutamatergic and GABAergic synaptic transmission onto the hippocampal CA1 pyramidal cells, while cholinergic intracellular  was dramatically reduced by the A_25-35 injection. Spatial memory of the water maze task was also impaired by the bilateral icv A_25-35 injections, while bilateral microinjections of the same dose of A_35-25 was ineffective in affecting the long-term synaptic modification evoked by associative activation of cholinergic and GABAergic inputs, the cholinergic intracellular , 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 A-induced memory decline.