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The team further showed that Npas4 is activated by excitatory synaptic activity. "Excitation turns on a program that says, 'this cell is getting excited, we need to balance that with inhibition,'" explains Greenberg, who now also chairs the Department of Neurobiology at Harvard Medical School.
Finally, the researchers bred live mice that lacked Npas4, and found evidence of neurologic problems--the mice appeared anxious and hyperactive and were prone to seizures.
Greenberg and colleagues are now trying to learn more about the wide variety of genes that Npas4 regulates, each of which could give clues to synapse development and reveal new treatment possibilities for neurologic disorders. "If you have your hand on a transcription factor such as Npas4, new genome-wide technology allows you to essentially identify every target of the transcription factor," says Greenberg. One such target is neurotrophic factor (BDNF), which Greenberg and colleagues previously showed to regulate the maturation and function of inhibitory synapses.
Children's researchers Takao Hensch, PhD, and Michela Fagiolini, PhD, also in the Neurobiology program, plan to study the Npas4-lacking mice to see if they have abnormalities in the initiation of critical periods; colleague Chinfei Chen, MD, PhD, will also study the mice, further probing how their synapses develop.
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