A Genetic Program Regulated by Neuronal Activity

In the 1980s Dr. Greenberg and his colleagues discovered that neuronal activity induces a genetic program that plays a key role in mediating brain development and function (Science 1986). Recent evidence from the laboratory indicates that mutations in components of the signaling network that regulates this gene program can lead to profound disruptions of cognitive function resulting in mental retardation and possibly autism. Over two decades, and under the auspices of the IDDRC since 1994, this laboratory has studied the activity-regulated gene program in considerable detail.  Greenberg and his colleagues identified a signaling network that conveys a calcium signal from cell surface calcium channels to the nucleus, where the modification of transcriptional complexes triggers the induction of new gene expression.  This characterization of activity-regulated genes has provided insight into an important new function of calcium channels, revealed how calcium signals are conveyed from the plasma membrane to the nucleus, and elucidated a number of the functions of activity-regulated genes (Science 1994, 1999, Cell 2000).  Additional accomplishments include the discovery of the role that the transcription factor CREB plays in mediating calcium signaling in the brain and the purification and characterization of CREB kinases that convey the calcium signal to the nucleus (Science 1996).

Greenberg and his colleagues have also contributed significantly to the understanding of the function of this activity-dependent gene program.  Through the development of knockout mice that lack specific Fos family members, they demonstrated that activity-regulated genes mediate adaptive neuronal responses that underlie animal behavior – in particular circadian entrainment the response of animals to drugs of abuse, and maternal nurturing. This work established that the activity- dependent gene program is essential for adaptive neuronal responses and provided the first evidence that maternal nurturing responses are genetically encoded. Other related studies provided some of the first mechanistic understanding of how synaptic activity promotes neuronal survival during development.