Calcium regulation of neuronal gene expression is crucial for synaptic plasticity and long-term memory. This study identifies three key points where calcium influx influences gene expression. The induction of brain-derived neurotrophic factor (BDNF) gene expression is regulated by the route of calcium entry, the pattern of phosphorylation of the transcription factor CREB, and the complement of active transcription factors recruited to the BDNF promoter. These findings refine the model of activity-induced gene expression in the brain, explaining how different neuronal stimuli activate distinct transcriptional responses. Calcium influx into neurons, triggered by synaptic activity, initiates signaling pathways that lead to gene expression. The entry of calcium through different channels, such as NMDA and L-type voltage-gated channels, influences the specificity of gene induction. The NMDA receptor is involved in early developmental processes, while L-type channels are more associated with sustained CREB phosphorylation and gene expression. The specificity of calcium entry is influenced by the physical association of signaling molecules with calcium channels, which affects the activation of CREB and subsequent gene transcription. CREB is a key transcription factor regulated by calcium signaling. Its phosphorylation at Ser-133 is essential for gene expression, and different signaling pathways, including CaMK and Ras/MAPK, contribute to this process. The activation of CREB is also influenced by other transcription factors, such as those binding to CaRE elements in the BDNF promoter. These factors work together to regulate BDNF expression, which is critical for neuronal survival and synaptic plasticity. The study highlights the importance of coordinated activation of multiple transcription factors in the BDNF promoter for efficient gene expression. This coordination ensures that BDNF is induced in response to specific stimuli, such as membrane depolarization, rather than other signals like cAMP elevation. Understanding these mechanisms provides insights into how neurons adapt to different stimuli and maintain long-term plasticity. Future research aims to further elucidate the molecular mechanisms underlying these processes.Calcium regulation of neuronal gene expression is crucial for synaptic plasticity and long-term memory. This study identifies three key points where calcium influx influences gene expression. The induction of brain-derived neurotrophic factor (BDNF) gene expression is regulated by the route of calcium entry, the pattern of phosphorylation of the transcription factor CREB, and the complement of active transcription factors recruited to the BDNF promoter. These findings refine the model of activity-induced gene expression in the brain, explaining how different neuronal stimuli activate distinct transcriptional responses. Calcium influx into neurons, triggered by synaptic activity, initiates signaling pathways that lead to gene expression. The entry of calcium through different channels, such as NMDA and L-type voltage-gated channels, influences the specificity of gene induction. The NMDA receptor is involved in early developmental processes, while L-type channels are more associated with sustained CREB phosphorylation and gene expression. The specificity of calcium entry is influenced by the physical association of signaling molecules with calcium channels, which affects the activation of CREB and subsequent gene transcription. CREB is a key transcription factor regulated by calcium signaling. Its phosphorylation at Ser-133 is essential for gene expression, and different signaling pathways, including CaMK and Ras/MAPK, contribute to this process. The activation of CREB is also influenced by other transcription factors, such as those binding to CaRE elements in the BDNF promoter. These factors work together to regulate BDNF expression, which is critical for neuronal survival and synaptic plasticity. The study highlights the importance of coordinated activation of multiple transcription factors in the BDNF promoter for efficient gene expression. This coordination ensures that BDNF is induced in response to specific stimuli, such as membrane depolarization, rather than other signals like cAMP elevation. Understanding these mechanisms provides insights into how neurons adapt to different stimuli and maintain long-term plasticity. Future research aims to further elucidate the molecular mechanisms underlying these processes.