Editors' ChoiceNeuroscience

No Fear, Notch Is Here

Sci. Signal.  02 Sep 2014:
Vol. 7, Issue 341, pp. ec235
DOI: 10.1126/scisignal.2005848

Memories are formed through changes in the structure and function of neuronal synaptic connections, and these changes are mediated by alterations in both gene expression and protein translation. Dias et al. found that the microRNA (miRNA) miR-34a–mediated suppression of the abundance of two proteins in the Notch signaling pathway was required for the consolidation of fear memories in mice. A microarray and quantitative gene expression analysis identified miR-34a as the most increased miRNA in the amygdala of adult mice shortly after fear conditioning, in which an auditory cue is associated with a mild foot shock. Infusing the basolateral amygdala with viruses that expressed miR-34a sponge sequences to sequester the miRNA and inhibit its activity impaired fear memory formation in mice. Bioinformatic pathway analysis identified ligands and receptors within the Notch signaling pathway as targets of miR-34a. Overexpressing miR-34a reduced the expression of a luciferase reporter containing the Notch1 3′-untranslated region in HEK293T (human embryonic kidney 293T) cells. After fear conditioning, the abundance of the transcript for Notch1 and the Notch1 ligand–encoding transcript Jag1 was decreased, whereas those of Notch2 and Dll1, encoding another Notch receptor–ligand pair that are also putative miR-34a targets, were unchanged. Blocking Notch signaling with either intraperitoneal administration of a γ-secretase inhibitor that crosses the blood-brain barrier or intracranial injection of a function-blocking Jag1 antibody into the basolateral amygdala increased the number of mice that froze in response to the auditory cue 24 hours after fear conditioning. In contrast, activating Notch signaling by infusing the basolateral amygdala with either the miR-34a sponge or lentiviral particles expressing the downstream Notch effector transcription factor Hes1 decreased the number of mice that froze to the auditory cue. The findings suggest that activating Notch signaling, either directly or through inhibition of miR-34a, might be a therapeutic strategy for people suffering from fear-related disorders, such as posttraumatic stress disorder.

B. G. Dias, J. V. Goodman, R. Ahluwalia, A. E. Easton, R. Andero, K. J. Ressler, Amygdala-dependent fear memory consolidation via miR-34a and Notch signaling. Neuron 83, 906–918 (2014). [PubMed]

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