We report a genome-wide expression analysis of cultured rat cortical neurons treated with specific pharmacological agents, a model with alterations in neuronal activity. Using the microarray approach in combination with microelectrode array (MEA) technology, we ascertained out of approximately 27,000 genes 248 activity-dependent genes, which encompass a large number of members of distinct families, including synaptic vesicle proteins, ion channels, signal transduction molecules, synaptic growth regulators, and others. These genes were further confirmed to be Ca2+-sensitive, largely regulated by Ca2+ influx through N-methyl-D-aspartate (NMDA) receptors, and partly through L-type voltage-gated Ca2+ channels (VGCCs). In addition, the dynamics of gene expression cascades, specifically and temporally regulated, and the pools of those downstream genes, selectively responded to particular routes of Ca2+ entry, were also elucidated, as well as the functional consequences of candidate genes associated with synaptic plasticity. Keywords: pharmacological agents, cortical neurons Overall design: pharmacological agents vs control