PT - JOURNAL ARTICLE AU - Pietro Baldelli AU - Jacopo Meldolesi TI - The transcription repressor REST in adult neurons: physiology, pathology, and diseases AID - 10.1523/ENEURO.0010-15.2015 DP - 2015 Jul 01 TA - eneuro PG - ENEURO.0010-15.2015 4099 - http://www.eneuro.org/content/early/2015/07/01/ENEURO.0010-15.2015.short 4100 - http://www.eneuro.org/content/early/2015/07/01/ENEURO.0010-15.2015.full AB - REST (also named NRSF), a transcription factor, is known to repress thousands of possible target genes, many of which are neuron-specific. To date, REST repression has mostly been investigated in stem cells and differentiating neurons. Current evidence demonstrates its importance in adult neurons as well. Low levels of REST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend on miRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induce REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains debated. Examples of CA1 hippocampal neuron protection upon depolarization and of neurodegeneration upon glutamate treatment and hypoxia have been reported. REST participation in psychiatric and neurological diseases has been shown, especially in Alzheimer’s and Huntington’s disease as well as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that conflicting results reported for the role of REST in physiology, pathology and disease depend on its complex, direct and indirect actions on many gene targets and on the diverse approaches employed during the investigations.Significance Statement: Analysis of the role of REST in adult neurons, before and after stimulation and under pathological conditions, is presented for the first time, along with the available information about the role that the transcription repressor appears to play in diseases, especially in Alzheimer's disease and epilepsy. The development of these studies in the next few years is anticipated.