Functional Organization Of The Basal Ganglia

National Institute Of Mental Health

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Abstract

Work during the fiscal year extended our prior research on the function of the basal ganglia in animal models of neurologic disorders. Our work was the first to demonstrate that there is an abnormal coupling of Drd1a dopamine receptors to activation of Extracellular Receptor Kinase (ERK1/2) in an animal model of Parkinson's Disease. Although activation of ERK1/2 is critical to ongoing synaptic plasticity in the glutamate-mediated cortical input to the striatum, coupling to the Drd1a-receptor is aberrant in the dopamine depleted striatum. During this past year we used a transgenic mouse model, which allowed a reversal of dopamine depeletion in the striatum, to show that aberrant Drd1a-coupled ERK1/2 activation is directly related to the level of dopamine input in the striatum ( Kim et al., 2006).[unreadable] [unreadable] In another study, we demonstrated aberrant coupling of a serotonin receptor (5HT2A) to activation of ERK1/2 in an animal model of Attention Deficity Hyperactivity Disorder (Brown and Gerfen, 2006). In this animal model, neonatal lesions of the nigrostriatal dopamine system are followed by a robust sprouting of serotonin fibers into the striatum, which does not occur with adult lesions in the PD model. When such neonatally lesioned animals become adults, 5HT2A-receptor agonists produce activation of ERK1/2. Whereas Drd1-receptor agonists produce ERK1/2 activation in both the neonatal and adult lesioned models, 5HT2A-receptor agonists produce such activation only in the neonatal lesioned animals. This finding suggests that in both ADHD and PD distinct mechanisms result in the aberrant activation of ERK1/2 in striatal direct pathway neurons.[unreadable] [unreadable] Further work on the cellular mechanisms underlying neurologic and pscyhiatric disorders is limited by the fact that neurons throughout the brain utilize common mechanisms for critical functions such as synaptic plasticity, whereas specific neural systems are affected in different disorders. A large part of the Laboratory is now working with the Gene Expression Nervous System Atlas (GENSAT) project ( funded by NINDS and NIMH ) to produce transgenic mice with Cre-recombinase under the regulation of promoters to drive expression in specific neuron populations. Our part of this work is to characterize the expression of Cre in the brains of such transgenic lines and to provide such lines to the Mutant Mouse Regional Resource Center (MMRRC) for distribution to the research community. In the past year we characterized 14 Cre driver lines and are in the process of characterizing 25-50 lines for the current year ( Gong et al., 2007)