Functional Characterization of Des-IGF-1 Action at Excitatory Synapses in the CA1 Region of Rat Hippocampus

1 Departments of Physiology and Pharmacology, 2 Roena Kulynych Center for Memory and Cognition Research, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina Submitted 28 July 2004; accepted in final form 2 March 2005 Insulin-like growth factor-1 (IGF-1) and growth hormone play a major role in the growth and development of tissues throughout the mammalian body. Plasma IGF-1 concentrations peak during puberty and decline with age. We have determined that chronic treatments to restore plasma IGF-1 concentrations to adult levels attenuate spatial learning deficits in aged rats, but little is known of the acute actions of IGF-1 in the brain. To this end, we utilized hippocampal slices from young Sprague-Dawley rats to characterize the acute effects of des-IGF-1 on excitatory synaptic transmission in the CA1 region. We observed a 40% increase in field excitatory postsynaptic potential (fEPSP) slope with application of des-IGF-1 (40 ng/ml) and used whole cell patch-clamp recordings to determine that this enhancement was due to a postsynaptic mechanism involving -amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) but not N -methyl- D -aspartate receptors. Furthermore, the enhancement was completely blocked by the broad-spectrum tyrosine kinase inhibitor, genistein (220 µM), and significantly reduced by the PI3K blockers wortmannin (1 µM) and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (10 µM), suggesting that the effect was predominantly dependent on PI3K activation. This characterization of the acute actions of des-IGF-1 at hippocampal excitatory synapses may provide insight into the mechanism by which long-term increases in plasma IGF-1 impart cognitive benefits in aged rats. Increases in AMPA receptor-mediated synaptic transmission may contribute directly to cognitive improvement or initiate long-term changes in synthesis of proteins such as brain-derived neurotrophic factor that are important to learning and memory. Address for reprint requests and other correspondence: J. L. Weiner, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157-1083 (E-mail: jweiner{at}wfubmc.edu )