Regulation of Gene Expression by Action-Potential Firing Patterns

All information in the nervous system is encoded in the pattern of neural impulse activity. Given that experience regulates nervous system structure and function, gene activity in neurons must be regulated by the pattern of neural impulse activity. We tested this hypothesis by stimulating nerve cells to fire impulses in different patterns by delivering electrical stimulation through platinum electrodes in specially designed cell culture dishes. After stimulation, we assayed global mRNA levels by microarray. The experiments revealed signaling pathways and gene-regulatory networks that respond selectively to appropriate temporal patterns of action potential firing in neurons. Temporal aspects of intracellular calcium signaling are particularly important in regulating gene expression according to neural impulse firing patterns in normal and pathological conditions. We are also analyzing the role of post-transcriptional gene expression mediated by mRNA stability and transport in hippocampal and dorsal root ganglion neurons. Our findings provide a deeper understanding of how nervous system development and plasticity may be regulated by information coded in the temporal pattern of impulse firing in the brain, which has relevance to chronic pain and regulating nervous system development by functional activity.

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Figure 1. An image of 13 different gene expression patterns.
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Figure 2. A snapshot of gene products that interact with each other.

Global gene expression profiling reveals that regulation of gene expression by specific patterns of action potential firing affects hundreds of genes of all functional categories. Thus, expression of many genes is continuously regulated simultaneously and differentially in a neuron in accordance with the action potential firing patterns experienced. Cultured embryonic DRG neurons were stimulated in multi-compartment chambers with specific patterns of action potentials. Stimulus parameters were developed that would produce similar or countervailing differences in the magnitude of Ca2+ release, but that differed in specific temporal features. In this case the stimulus frequency was held constant at 10 Hz, and we applied 2 types of intermittent pulse train stimuli (to separate culture preparations) of 1.8 and 9 sec duration (respectively), repeated at 1 and 5 min inter-burst intervals (respectively) (pattern 1:18/1, pattern 2: 90/5). Pulse train stimulation was delivered for 120 min, therefore delivering a total of 2160 action potentials for each stimulus pattern. For each pattern (either 18/1 or 90/5). Select genes were then analyzed using the Ingenuity pathway analysis software to generate a snapshot of gene products that interact with each other, either directly or indirectly, based on published literature and the NCBI database. It is clear that these two different patterns of action potentials produce different gene expression outputs, despite delivering the same total number of action potentials over a 120 min delivery period.

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