"Neuronal excitation-transcription coupling in health and disease"

Neuroscience Seminar Series: Mark Dell'Acqua, Ph.D

Long-term information storage mediated by synaptic plasticity in the brain requires modification of the neuronal transcriptome in response to changes in neuronal activity. This process, known as excitation-transcription (E-T) coupling, can be initiated by receptors and ion channels at distal synaptic sites in dendrites, to trigger long-range signaling via protein kinases and phosphatases to transcription factors, such as CREB and NFAT, in the nucleus in the cell soma. Importantly, E-T coupling is required for normal brain development and learning and memory, and disruption of synapse-to-nucleus signaling is implicated in neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Through employing a variety of optical stimulation and imaging approaches in combination with genetic and pharmacological manipulations, we previously found that glutamate receptors activated on distal dendrites can initiate L-type voltage-gated Ca2+ channel (LTCC)-dependent Ca2+ spikes that rapidly propagate from dendrites to the soma to promote calcineurin (CaN) phosphatase-mediated activation NFAT. Furthermore, this E-T coupling pathway is organized by an AKAP scaffold protein that recruits CaN, and also the kinase PKA, to glutamate receptors and LTCCs to control both upstream Ca2+ signal generation in dendrites and downstream propagation to the soma to promote NFAT translocation to the nucleus. Importantly, new findings will be presented indicating that these AKAP-CaN-NFAT synapse-to-nucleus signaling mechanisms are aberrantly engaged by synaptotoxic amyloid-beta oligomers in Alzheimer’s disease and are disrupted by de novo mutations in the human PPP3CA gene encoding CaNAalpha that cause a developmental epileptic encephalopathy.

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