Synaptic Connectivity and Neurodegeneration
Prof. Dr. Dr. Pierluigi Nicotera
Scientific Director and Group Leader
Venusberg-Campus 1, Gebäude 99
(ehemals Sigmund-Freud-Str. 27)
53127 Bonn

office-nicotera@dzne.de
 +49 228 43302-602

Areas of investigation/research focus

Synapses are cellular structures that regulate the transfer of information between neurons. Their formation and remodeling determines neuronal connectivity and influences higher brain functions. Age-related loss of synapses undermines neural circuits, leading to progressive functional and structural changes of the brain that contribute to cognitive deficits in older adults. Consistently, impairment of synaptogenesis as well as excessive spine pruning can lead neurodegenerative conditions. Thus, investigating the molecular pathways underlying physiological and non-physiological synaptic remodeling may shed light into the pathogenesis of neurodegenerative diseases. In line with this hypothesis, we showed that, while the disruption of the synaptic exocytotic machinery is sufficient to trigger neuronal degeneration, restoring vesicle recycling could prevent dendritic spine loss and neurodegeneration in models of Huntington’s disease (Richards P. et al, 2011). Furthermore, we addressed the importance of spatiotemporal regulation of calcium (Ca2+) transients in neuronal plasticity. We demonstrated that activity-evoked intracellular Ca2+ remodeling regulates long-term synaptic physiology and neuronal plasticity (Ziviani E. et al, 2010; Lippi G. et al, 2011). Another recent line of research focuses on the histone variant H3.3 and its loading machinery. We showed that H3.3 establishes transcriptional patterns underlying activity-dependent chromatin changes in neurons as well as pro-longevity signaling pathways in metazoan (Michod D. et al, 2012; Piazzesi A. et al, 2016). Our program aims to define additional epigenetic factors that contribute to synaptic maintenance and plasticity, since they may be relevant as molecular targets for translational strategies in humans.

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Ca2+ remodeling and neuronal plasticity

Spatiotemporal regulation of Ca2+ transients critically orchestrates local signal transduction and modulates synaptic compartments, leading to distinct forms of neuronal plasticity. The initial Ca2+ influx through plasma membrane channels facilitates the establishment of functionally distinct microdomains. Then, the subsequent Ca2+ release from the endoplasmic reticulum (ER) amplifies the signal via a positive feedback mechanism known as calcium-induced calcium release (CICR). Two major classes of channels have been implicated as main mediators of CICR in excitable cells: Ryanodine receptors (RyRs) and inositol (1,4,5)-triphosphate receptors (IP3Rs). Ryanodine receptor 2 (RyR2) is the most abundant isoform in the brain and is involved in learning and memory processes, aging and neurodegenerative disorders, including Alzheimer’s disease. We showed that long-term stimulation with the psychoactive alkaloid nicotine induces a RyR2-dependent transcriptional pattern that is required for neuronal plasticity. In this context, one line of research focuses to determine the relevance of Ca2+ remodeling in gene expression programs that influence cognitive function and behavioural processes. Moreover, we aim to define the underlying epigenetic factors that contribute to synaptic plasticity in a RyR2-dependent fashion.

Key Publications

Berliocchi L, Fava E, Leist M, Horvat V, Dinsdale D, Read D, Nicotera P. Botulinum neurotoxin C initiates two different programs for neurite degeneration and neuronal apoptosis. J Cell Biol. 2005 Feb 14; 168:607-18.
Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, Naldini L, Rizzuto R, Carafoli E, Nicotera P. Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell. 2005 Jan 28; 120:275-85.
Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med. 1997 Apr 21; 185:1481-6.
Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A. 1995 Aug 01; 92:7162-6.
Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron. 1995 Oct 01; 15:961-73.

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