IGF-1 in Brain Growth and Repair Processes

Abstract

This chapter addresses the role of insulin‐like growth factor 1 {(IGF‐1)} and the {IGF‐1} receptor {(IGF1R)} in brain development, injury response, and aging. We concentrate mainly on recent information from murine model systems, with consideration of interesting and relevant data from invertebrates and humans. {IGF‐1} and its cognate receptor are both highly expressed in the developing brain, supporting both autocrine and paracrine activity for this anabolic peptide. {IGF‐1} deletion or inhibition during brain development attenuates brain growth, with reductions in both cell number and cell size. Cell numbers are notably reduced in the olfactory system, the dentate gyrus of the hippocampus, and the striatum. Brain volume is globally decreased due to a loss of neuropil, with significant reductions in neuronal soma volume, dendritic length and complexity, and synapse number. Myelination is reduced in proportion to the decreases in neuron number and nerve processes in the {IGF‐1‐null} brain. Conversely, transgenic {IGF‐1} overexpression results in increased brain size with increases in cell number, cell size, and dendrite growth with proportionate increases in myelination. Metabolic activity as measured by glucose utilization is significantly decreased in the {IGF‐1‐null} brain and increased in the transgenic {IGF‐1‐overexpressing} brain. {IGF‐1} deletion in humans is associated with mental retardation and sensorineural deafness. {IGF‐1} deletion is also associated with deafness in mice, but no other obvious neurological or behavioral phenotypes have been identified. {IGF‐1} prevents neuronal death in response to a variety of insults in vitro, but cell death appears to be a minor effect in the {IGF‐1‐null} brain. {IGF‐1's} physiological effects in brain depend on when and where the peptide is expressed. For example, {IGF‐1} is expressed in an olfactory neuron germinal zone early in development, enhancing proliferation of these neurons, which are correspondingly reduced in number in the {IGF‐1‐null} mouse. {IGF‐1} is expressed in long‐axon projection neurons at a later, postmitotic stage, promoting somatic and dendritic growth for these neurons, which are normal in number but small with hypotrophic dendritic arbors in the {IGF‐1‐null} brain. Increased circulating or brain {IGF‐1} is associated with increased hippocampal neurogenesis in adult rodents, and treatment with exogenous {IGF‐1} may protect against neurodegeneration in response to brain injury. {IG…