Aging of synapse structure and function
Prof. Dr. Stephan Sigrist
Group Leader
Takustr. 6
14195  Berlin

stephan.sigrist@dzne.de
 +49 30 838-56940

Forschungsschwerpunkte

All animals form memories to adapt their behavior in a context-dependent manner. With increasing age, however, forming new memories becomes less efficient. While synaptic plasticity promotes memory formation, the etiology of age-induced memory formation (AMI) remained enigmatic. To overcome the challenges associated with disentangling causative factors of AMI from adaptive/protective changes during aging, the Sigrist group uses an olfactory conditioning paradigm in Drosophila. This allows them to combine mechanistic analysis of highly conserved neuronal circuit elements with an efficient genetic and cell biological experimental access for studying aging and memory.

Previous work of the Sigrist lab showed that pharmacological and genetic restoration of autophagy protected from age-induced memory impairment in Drosophila (Gupta et al., 2013). In addition, they recently showed that restoration of autophagy operates directly at the synaptic level and kept synapses in an operational space compatible with forming long-term memories fighting the normally occurring up-shift of presynaptic structure and function (Gupta et al., 2016). How mechanistically autophagic regulations intersect with synaptic plasticity mechanisms, however, remains an interesting but unsolved question. Their preliminary results now implicate the evolutionary highly conserved NPY-signaling in communicating in between the autophagic status and synaptic plasticity in a non-cell autonomous fashion.

They find that i) genetic impairment of autophagy already in young animals reproduces the synaptic changes normally typical for aged animals, ii) that defective autophagy reduces NPY-signaling and iii) that genetic elimination of NPY-signaling reproduces the age-typical synaptic phenotypes in young animals. Notably, age-modulation of hypothalamic NPY-signaling is suspected to contribute to age- associated learning and cognitive deficits. Thus, our results identify NPY-signaling, connecting autophagic signaling with a brain-wide synaptic metaplasticity event gating memory formation, as a promising spot of therapeutic intervention to ameliorate AMI. Future work also in rodent models together with the Schmitz and Garner groups will seek to advance the mechanistic understanding of AMI. In preparation of these efforts, we recently characterize presynaptic signaling in rodents together with the Schmitz lab (Grauel et al., 2016).

Recently, the group provides evidence that Spermidine boosts autophagy to protect from age-associated upshift in the ultrastructural size and release function of the presynaptic active zone (Fig. 1) (Bhukel et al., 2019).

Key Publications

Bhukel A, Beuschel CB, Maglione M, Lehmann M, Juhász G, Madeo F, Sigrist SJ. Autophagy within the mushroom body protects from synapse aging in a non-cell autonomous manner. Nat Commun. 2019 Mar 21; 10:1318. doi: 10.1038/s41467-019-09262-2
Gupta VK, Pech U, Bhukel A, Fulterer A, Ender A, Mauermann SF, Andlauer TF, Antwi-Adjei E, Beuschel C, Thriene K, Maglione M, Quentin C, Bushow R, Schwärzel M, Mielke T, Madeo F, Dengjel J, Fiala A, Sigrist SJ. Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release. PLoS Biol. 2016 Sep 29; 14:e1002563. doi: 10.1371/journal.pbio.1002563
Bohme MA, Beis C, Reddy-Alla S, Reynolds E, Mampell MM, ..., Sigrist SJ. Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca2+ channel-vesicle coupling. Natu Neurosci. 2016 Jan 01; 19:1311-20. doi: 10.1038/nn.4364
Gupta VK, Scheunemann L, Eisenberg T, Mertel S, Bhukel A, Koemans TS, Kramer JM, Liu KS, Schroeder S, Stunnenberg HG, Sinner F, Magnes C, Pieber TR, Dipt S, Fiala A, Schenck A, Schwaerzel M, Madeo F, Sigrist SJ. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci. 2013 Oct 01; 16:1453-60. doi: 10.1038/nn.3512
Karen S. Y. Liu, Matthias Siebert, Sara Mertel, Elena Knoche, Stephanie Wegener, Carolin Wichmann, Tanja Matkovic, Karzan Muhammad, Harald Depner, Christoph Mettke, Johanna Bückers, Stefan W. Hell, Martin Müller, Graeme W. Davis, Dietmar Schmitz, Stephan J. Sigrist. RIM-binding protein, a central part of the active zone, is essential for neurotransmitter release. Science. 2011 Dec 15; 334:1565-1569. doi: 10.1126/science.1212991

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