Université de Bordeaux
BrainConf: Synaptic Plasticity27-30 September, 2022 - Bordeaux

Mark Dell'Acqua

Mark Dell'Acqua, Department of Pharmacology, University of Colorado School of Medicine, USA


Regulation of postsynaptic structural plasticity by L-type Ca2+-channel-mediated remodeling of the dendritic spine ER


Strong synaptic input to hippocampal pyramidal cell dendrites can activate postsynaptic NMDA-type glutamate receptors (NMDARs) and L-type voltage-gated Ca2+ channels (LTCCs) resulting in the generation dendritic plateau potentials/complex spikes. These complex spikes produce Ca2+ signals that facilitate the induction of both functional long-term potentiation of synaptic strength (LTP) and structural potentiation of dendritic spine size (sLTP) locally in dendrites.  Using laser uncaging of MNI-glutamate to stimulate single dendritic spines, we found that LTCC opening downstream of NMDARs promotes Ca2+-induced Ca2+ release (CICR) from the nearby dendritic endoplasmic reticulum (ER).  This LTCC-mediated CICR results in local depletion of ER Ca2+ stores in dendrites near stimulated spines that in turn activates the ER Ca2+ sensor stromal interaction molecule 1 (STIM1). The efficacy of LTCC coupling to CICR and STIM1 activation in dendrites is prominently tuned by protein kinase A (PKA)-mediated enhancement of LTCC function that is opposed by calcineurin (CaN) phosphatase activity, with both PKA and CaN being scaffolded to the channel by A-kinase anchoring protein (AKAP) 79/150. Importantly, LTCC activation of STIM1 in hippocampal neurons coordinates a series of downstream signaling events that:  1) further amplify local, postsynaptic Ca2+ responses via engagement of store-operated Ca2+ entry (SOCE) mediated by Orai1 channels and 2) control the heterosynaptic spatial dynamics and long-term temporal maintenance of sLTP in dendrites through remodeling of the spine ER, independent of Orai1-mediated Ca2+ influx. These studies, both published and unpublished, implicate LTCC activation of STIM1 as a novel mechanism supporting long-term maintenance of postsynaptic structural plasticity.


From my graduate training on G protein-coupled receptors with Ernest Peralta at Harvard University and postdoctoral training on kinase/phosphatase signaling with John Scott at the Vollum Institute, I have broad expertise studying second messenger and phosphorylation signaling. Over the last 22 years, my laboratory at University of Colorado Anschutz Medical Campus helped establish the importance of A-kinase anchoring protein (AKAP) 79/150 anchoring of the cAMP-dependent protein kinase (PKA) and the Ca2+-dependent protein phosphatase 2B-calcineurin (CaN) in regulating neuronal L-type voltage gated Ca2+ channels, AMPA and NMDA glutamate receptors, and GABAA receptors during LTD and LTP synaptic plasticity. We are investigating these processes during normal plasticity as well as in brain disorders, including Alzheimer’s disease, cerebral ischemia, Down syndrome, and autism.  We employ a range of experimental methods from quantitative fluorescence imaging to electrophysiology to behavioral analyses. In particular, my laboratory has expertise using electrophysiology, optical manipulation, and advanced fluorescence imaging methods to study glutamate receptors, L-type Ca2+ channels, GABAA receptors, NFAT-dependent transcriptional signaling, membrane trafficking, and dendritic spine structure during synaptic plasticity.      

Website: medschool.cuanschutz.edu/pharmacology/faculty/primary-faculty/mark-dell'acqua-phd