Collaborations

The Neurobiology of Forgetting - Spontaneous Synaptic Remodeling, Cortical Representation Stability, Memory retention and Behavioral Flexibility

Simon Rumpel , Noam E. Ziv , Naama Brenner , Camin Dean , Matthias Kaschube , Nils Brose  

German Israeli Project Cooperation (DIP); Research Cooperation Lower Saxony – Israel

Why do we forget? The fascinating phenomenon of forgetting, originally studied by experimental psychologists and later by experimental, computational, and theoretical neuroscientists, has been a focus of research for over a century. Although forgetting is often regarded as detrimental, in particular in association with pathologies such as dementia, we now know that it is crucially important for behavioral flexibility – the adaptation to changing environments or the generalization of acquired knowledge – as well as for mitigating traumatic events. 

For decades, forgetting has been viewed as a consequence of ongoing life experiences, which interfere with prior memories, overwrite them or obfuscate their retrieval. More recently, forgetting has also been shown to involve biological mechanisms that actively and selectively ‘erase’ undesirable information. Much of this work has focused on synapses, the specialized junctions that interconnect nerve cells into vast and complex networks. This focus stems from the widely accepted doctrine that changes to synapses represent the main mechanism by which nervous systems learn new tasks and store new information. This doctrine is also associated with an implicit assumption that synaptic properties, when not driven to change by physiological cues or ‘erasure’ mechanisms, will persist indefinitely. Yet, unlike most human-built storage devices, in which information typically persists until actively erased, persistence of synaptic properties cannot be taken for granted: Synapses are made of dynamic, short-lived (days) components that continuously move in, out and between synapses over time scales of minutes and hours. Indeed, these dynamics drive spontaneous changes in synaptic properties which are of the same magnitude as those driven by physiological signals. While attempts have been made to reconcile this volatility of synaptic connections with canonical views of synapses as information storage devices, a straightforward possibility is that spontaneous changes in synaptic connection might simply drive forgetting. Surprisingly, this evident possibility has hardly been explored. 

The overall goal of this project is thus to explore relationships between spontaneous synaptic remodeling, forgetting and behavioral flexibility. Its major thrust is to (1) devise perturbations that specifically and selectively affect spontaneous synapse remodeling rates, (2) introduce the most effective molecular modifications into mouse models, (3) validate their effects on synaptic remodeling dynamics in vivo, (4) examine how these perturbations affect the stability of cortical representations in these animals, and (5) examine by behavioral testing, how these perturbations affect memory, forgetting, and behavioral flexibility. The project therefore is a  collaborative, multilevel (molecular, synaptic, network, behavior) program which deeply integrates experimentation, advanced analytical methods and theory.  

Syntophagy - Membrane Trafficking Processes Underlying Presynaptic Proteostasis 

Daniela Dieterich,  Noam E. Ziv, the Syntophagy Consortium

German Research Foundation (DFG) Research unit 5228, “Syntophagy”

Neurons are polarized cells with a complex cytoarchitecture. Typically, the number of synapses is huge, their molecular makeup extraordinarily complex, and their distance from the cell body, where most protein synthesis occurs, can be enormous. While synapses can persist for months and even years. Their proteinaceous components, can become dysfunctional after much shorter periods, and thus must be continuously removed and degraded. Moreover, due to the membrane dynamics associated with synaptic transmission, maintaining the molecular composition of presynaptic sites can be even more challenging. How protein turnover is regulated in axons and axon terminals, and whether this occurs locally (i.e. at the synapse) or in the soma is a key cell biological question. Currently, there is a surprising paucity of data on necessities for and mechanisms of protein replacement at presynaptic sites. Gaps in our knowledge concern, for example, which degradative pathways are involved, how proteins are sorted for certain degradative mechanisms, how sorting itself is accomplished, how different pathways contribute to the presynaptic proteome, which signals direct proteins into a given pathway, how synaptic activity affects degradation, how cross-talk is regulated, and which presynaptic sensor mechanisms identify protein 'damage'. A thorough understanding is also lacking on how the different modes of protein degradation interconnect with protein replenishment mechanisms. 

The Syntophagy consortium consist of a large team of expert synaptic biologists who apply different methodologies and competences to the problem of presynaptic proteostasis.  Within this consortium , the Dieterich and Ziv labs are carrying out a collaborative project on the roles of autophagy in the clearance of protein complexes and aggregates. Moreover, as significant evidence suggests that aging is associated with impaired protein clearance, and that manipulations that augment autophagy increase life-span and rejuvenate multiple physiological processes, the labs are studying the degrees to which manipulations of autophagy affect  presynaptic protein turnover, activity, and synaptic viability. 

The roles of N-terminal ubiquitination in the etiology of Huntington's disease

Huu Phuc Nguyen, Noam E. Ziv,  Aaron Ciechanover

The German Israeli Foundation For Scientific Research & Development (GIF); The German Research Foundation (DFG); The Rappaport Family Institute for Research in the Medical Sciences; The Allen and Jewel Prince Center for Neurodegenerative Disorders of the Brain

Huntington’s disease (HD) is caused by a glutamine repeat expansion in the protein huntingtin. Mutated huntingtin (mHtt) forms aggregates whose impacts on neuronal survival are still debated. In this collaborative project, the importance of ubiquitination of mutated huntingtin at its N terminus on cell viability and disease progression is studied. In prior studies, using a novel HD rat model, we identified two lysine residues, 6 and 9, in the first exon of mHtt that are specifically ubiquitinated in striatal and cortical brain tissues of mHtt-transgenic animals. Using very long term imaging we find that when these two lysines are left intact, mutated huntingtin fragments are gradually sequestrated into peripheral, mainly axonal aggregates, concomitant with dramatic reductions in cytosolic mHtt levels and enhanced neuronal survival. in-situ pulse-chase imaging revealed that aggregates continually gain and lose mHtt, in line with these acting as mHtt sinks at equilibrium with cytosolic pools. Mutating the two aforementioned N-terminal lysines in a manner that prohibits ubiquitination at these sites suppresses peripheral aggregate formation and reductions in cytosolic mHtt, promotes nuclear aggregate formation, stabilizes aggregates and leads to pervasive neuronal death. These studies demonstrated the capacity of aggregates of potentially toxic proteins forming at peripheral locations to sequester these away and support a crucial role for N-terminal ubiquitination in promoting aggregation and delaying neuronal death. These observations served as the basis for the creation of transgenic animals harboring either mutated huntingtin or the same mutated huntingtin moiety in which these two lysines were mutated in a manner that prohibits their ubiquitination.  Experiments on these animal are ongoing, but already provide strong support for the findings described above.

Additional Collaborations, Present and Past

• Shimon Marom (Technion)

• Naama Brenner (Technion)

• Members of the Network Biology Labs (Technion)

• Craig Garner (Stanford, DZNE) 

• Eckart Gundelfinger (Magdeburg)

• Susanne Schoch, Inst. of Neuropathology, Bonn

• Kobi Rosenblum (Haifa University)

• Antoine Triller (IBENS-ENS)