Abstract
BackgroundBrain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated.Methodology/Principal FindingsIn this study, we assessed the relative contributions of multipartite intracellular signaling pathways to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a) and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365). Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS), phosphotidylinositol-3-kinase (PI3K), and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEK-dependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity.ConclusionsThese results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression.
Highlights
Medium-sized spiny striatal neurons (MSNs) comprise .90% of all striatal neurons and serve the functions of integrating and transmitting information from the cerebral cortex to the output nuclei of the basal ganglia [1,2,3]
These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important Brain-derived neurotrophic factor (BDNF)-dependent striatal functions that are fulfilled through the positive regulation of gene expression
In order to achieve a comprehensive measure of acute gene expression responses to BDNF in striatal neurons, we used microarray gene expression profiling to assay global mRNA expression differences following 3 h treatment of primary striatal cultures with BDNF
Summary
Medium-sized spiny striatal neurons (MSNs) comprise .90% of all striatal neurons and serve the functions of integrating and transmitting information from the cerebral cortex to the output nuclei of the basal ganglia [1,2,3]. This circuit is crucial for many important functions, such as the regulation of voluntary movement, and is involved in human neurodegenerative and neuropsychiatric disorders. The striatum is highly innervated by BDNF-releasing synapses. Brain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Many essential aspects of BDNF responses in striatal neurons remain to be elucidated
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