TRANSGENIC MOUSE MODELS OF MENTAL RETARDATION

Children'S Hospital Of Philadelphia, Philadelphia PA

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Abstract

Our research focuses on the role played by the cAMP/PKA/CREB/i intracellular pathway in neuronal development, synaptic plasticity, learning and memory. Transgenic techniques are used to express genes that have been designed to inhibit or activate this signal transduction pathway. The cAMP/PKA/CREB pathway is genetically altered in two human disorders linked to mental retardation: Albright, Hereditary Osteodystrophy (AHO) and Rubinstein-Taybi syndrome. AHO is characterized by heterozygous inactivation of the stimulatory subunit of the guanine nucleotide-binding protein (G protein), which couples multiple cell-surface receptors (e.g., D1/D5 dopamine receptors) to the protein (G protein), which couples multiple cell-surface receptors (e.g., D1/D5 dopamine receptors) to the cAMP/PKA/CREB pathway. Rubinstein-Taybi syndrome has been linked to mutations in CREB- binding protein, which mediates cAMP-regulate gene expression by interacting with CREB (Petrij et al., 1995). Our earlier research has shown that PKA is critically involved in hippocampus-dependent forms of long-term memory. Synaptic plasticity, the experience dependent change in the strength of synapses in the hippocampus and other regions of the brain, may underlie memory storage and play a critical role in mental retardation. PKA plays a central role in long-lasting forms of synaptic plasticity in the hippocampus (Abel et al., 1997). Thus, the cAMP/PKA/CREB pathway is involved in learning and memory, and disruption of elements of this pathway can lead to mental. Our proposal is to use new genetic techniques that permit precise manipulation of the cAMP/PKA/CREB pathway in order to create transgenic mice that may serve as animal models of mental retardation. These mice will enable us to study the molecular, behavior and electrophysiological effects of interfering with the Gsalpha signaling pathway and may provide insight into the cognitive impairments that characterize mental retardation. Our studies will involve the following Specific Aims: Specific Aim 1: To create transgenic mice in which Gsalpha-mediated transduction is inhibited in a spatially and temporally restricted manner. Specific Aim 2: To use these transgenic mice to determine the role of Gs and the cAMP/PKA/CREB pathway in the acquisition, consolidation, retrieval and extinction of memory. Specific Aim 3: To use these transgenic mice to determine the role of Gs in the different phases of synaptic plasticity in the hippocampus, especially long-lasting forms of synaptic plasticity.