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

Abstract

characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus. J Neurophysiol 94: 247-254, 2005; doi:10.1152/jn.00768.2004. 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 M), and significantly reduced by the PI3K blockers wortmannin (1 M) and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (10 M), 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.

Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects

“…Naturally, we should envisage the biological role of serum IGF-I on brain function as a continuum ranging from acute to long-term effects on brain cells. In this regard, although we cannot yet establish a mechanistic link between acute and long-term actions of IGF-I on glutamatergic transmission, it is tempting to relate its reported acute effects on glutamate receptor function [39][40][41][42][43][44][45] or in intraneuronal Ca 2 þ mobilization [46][47][48] to long-term increases produced by IGF-I on glutamatergic receptor levels. 49,50 At any rate, since pulse-paired facilitation was not modified in LID hippocampal slices, presynaptic alterations may be ruled out, leaving postsynaptic actions of IGF-I as the most likely mechanism involved in its trophic action on glutamatergic transmission.…”

Epileptiform Activity Induces Vascular Remodeling and Zonula Occludens 1 Downregulation in Organotypic Hippocampal Cultures: Role of VEGF Signaling Pathways

“…Inhibition of VEGFR-2 signaling pathways. We inhibited VEGF-dependent signaling pathways using the following specific inhibitors, already used on rat brain slices (Selvatici et al, 2003;Ramsey et al, 2005;Dahmani et al, 2007): (1) Src pathway with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine (PP2) (10 M), and its inactive analog (PP3, 10 M), as control; (2) phosphatidylinositol 3-kinase (PI3K) with 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) (10 M); and (3) PKC with 2- [1-(3-dimethylaminopropyl)-1 H-indol-3-yl]-3-(1 H-indol-3-yl)maleimide (Bis 1) (1 M). All inhibitors (Calbiochem Merk Chemicals) were dissolved in DMSO.…”

The mood stabiliser lithium suppresses PIP3 signalling in Dictyostelium and human cells

“…These results have implications beyond the regulation of chemotaxis and could explain the therapeutic efficacy of lithium in the treatment of bipolar disorder. PIP 3 signalling in the nervous system is important for axonal guidance, synaptogenesis and synaptic transmission (Zhou et al, 2004;Ramsey et al, 2005;Chadborn et al, 2006;Martin-Pena et al, 2006;Xu et al, 2007), and mice with elevated PIP 3 levels suffer seizures (Backman et al, 2001). Lithium might, therefore, alter these processes through an …”