Npas4 Regulates Excitatory-Inhibitory Balance within Neural Circuits through Cell-Type-Specific Gene Programs

• Published in: Cell 2014-05, Vol.157 (5), p.1216-1229
• Main Authors: Spiegel, Ivo, Mardinly, Alan R., Gabel, Harrison W., Bazinet, Jeremy E., Couch, Cameron H., Tzeng, Christopher P., Harmin, David A., Greenberg, Michael E.
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Culture Techniques; Embryo, Mammalian - cytology; Gene Expression Regulation; genes; Mice; Mice, Knockout; neural networks; neurons; Neurons - metabolism; neuroplasticity; Synapses - metabolism; synaptic transmission; transcription (genetics); transcription factors; Transcription, Genetic
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.03.058

The nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response. [Display omitted] •Inducible gene programs are adapted to reflect the function of a neuron in a circuit•Neuronal activity induces a distinct transcriptional response in inhibitory neurons•Npas4 promotes development of excitatory synapses on SST-positive inhibitory neurons•Npas4 activates a set of inducible genes in SST neurons that function at synapses Activity induces the same set of early transcription factors in inhibitory neurons as it does in excitatory ones, but the downstream targets in each cell type differ in a manner that likely preserves an excitatory-inhibitory balance in cortical circuits.