Since its initial characterization over 20 years ago, there has been intense and unwavering interest in understanding the role of the transcription factor cAMP-responsive element binding protein (CREB) in a nervous system physiology. Through an array of experimental approaches and model systems, researchers have begun to unravel the complex and multifaceted role of this transcription factor in such diverse processes as neurodevelopment, synaptic plasticity, and neuroprotection. Here we discuss current insights into the molecular mechanisms by which CREB couples synaptic activity to long-term changes in neuronal plasticity, which is thought to underlie learning and memory. We also discuss work showing that CREB is a critical component of the neuroprotective transcriptional network, and data indicating that CREB dysregulation contributes to an array of neuropathological conditions.

Inducible gene expression plays a central role in neuronal plasticity, learning, and memory, and dysfunction of the underlying molecular events can lead to severe neuronal disorders. In addition to coding transcripts (mRNAs), non-coding microRNAs (miRNAs) appear to play a role in these processes. For instance, the CREB-regulated miRNA miR132 has been shown to affect neuronal structure in an activity-dependent manner, yet the details of its physiological effects and the behavioral consequences in vivo remain unclear. To examine these questions, we employed a transgenic mouse strain that expresses miR132 in forebrain neurons. Morphometric analysis of hippocampal neurons revealed that transgenic miR132 triggers a marked increase in dendritic spine density. Additionally, miR132 transgenic mice exhibited a decrease in the expression of MeCP2, a protein implicated in Rett Syndrome and other disorders of mental retardation. Consistent with these findings, miR132 transgenic mice displayed significant deficits in novel object recognition. Together, these data support a role for miR132 as a regulator of neuronal structure and function, and raise the possibility that dysregulation of miR132 could contribute to an array of cognitive disorders.

Within the central nervous system, microRNAs have emerged as important effectors of an array of developmental, physiological, and cognitive processes. Along these lines, the CREB-regulated microRNA miR-132 has been shown to influence neuronal maturation via its effects on dendritic arborization and spinogenesis. In the mature nervous system, dysregulation of miR-132 has been suggested to play a role in a number of neurocognitive disorders characterized by aberrant synaptogenesis. However, little is known about the inducible expression and function of miR-132 under normal physiological conditions in vivo. Here, we begin to explore this question within the context of learning and memory. Using in situ hybridization, we show that the presentation of a spatial memory task induced a significant ~1.5-fold increase in miR-132 expression within the CA1, CA3, and GCL excitatory cell layers of the hippocampus. To examine the role of miR-132 in hippocampal-dependent learning and memory, we employ a doxycycline-regulated miR-132 transgenic mouse strain to drive varying levels of transgenic miR-132 expression. These studies revealed that relatively low levels of transgenic miR-132 expression, paralleling the level of expression in the hippocampus following a spatial memory task, significantly enhanced cognitive capacity. In contrast, higher (supra-physiological) levels of miR-132 (>3-fold) inhibited learning. Interestingly, both the impaired cognition and elevated levels of dendritic spines resulting from supra-physiological levels of transgenic miR-132 were reversed by doxycycline suppression of transgene expression. Together, these data indicate that miR-132 functions as a key activity-dependent regulator of cognition, and that miR-132 expression must be maintained within a limited range to ensure normal learning and memory formation.

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