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 Presynaptic Plasticity


The efficacy of neurotransmitter release importantly determines signal processing within neuronal networks, being regulated during virtually all forms of neuronal plasticity. However, how is plasticity of presynaptic function achieved at the molecular level is not fully understood. The main focus of the group is the study of molecular mechanisms and cellular pathways that mediate the presynaptic functional remodeling during experience-induced, homeostatic and pathological neuronal plasticity. We investigate the plasticity-induced molecular rearrangements of presynaptic release machinery, synaptic vesicle pools and membrane channels. Moreover, we are also interested in studying cellular signaling driving reconfiguration of gene expression, which induces persistent changes in neuronal function. The ultimate aim of our research is the identification of cellular processes and effector proteins that may represent a target of intervention in order to prevent maladaptive presynaptic plasticity that occurs under neuropathological conditions.

The cytomatrix at the active zone (CAZ), which is involved in the regulation of neurotransmitter release, is the major substrate for presynaptic plasticity. During homeostatic scaling, a form of slow synaptic plasticity, a profound reorganization of presynaptic cytomatrix occurs. Our previous data indicate that both degradation of CAZ components by proteasome (1) and de novo protein synthesis (2) are involved. To study molecular remodeling of CAZ during fast plasticity we have established two neuropathology-related models that induce rapid changes of presynaptic function i.e. (3) treatment with ketamine, effective antidepressant used in the treatment of major depressive disorder and (4) Amyloid β (Aβ)-dependent modulation of presynaptic efficacy. The understanding of molecular mechanisms and signaling cascades that mediate these processes are the main aim of our research group.

Currently, members of our lab work on following projects:

Role of ubiquitin proteasome system in the experience-induced and homeostatic plasticity of neurotransmitter release

Sandra Fienko

The ability of synapses to modulate their functionality importantly contributes to neuronal plasticity, the cellular process underlying the complex brain functions such as learning and memory formation.  In our previous work we have demonstrated that changes in efficacy of neurotransmitter release are connected with significant molecular remodeling of the release machinery and that ubiquitin-proteasome system (UPS) plays an important role in this process (Lazarevic et al., 2011). In particular, we have shown that the specificity and overall activity of synaptic UPS is tightly regulated by neuronal activity. Despite the fact that several important presynaptic proteins were identified to be substrates of UPS, how the UPS contributes to synaptic plasticity remains unknown. Recently, we found that the ubiquitin-ligating enzyme SIAH interacts with the presynaptic scaffolding proteins Bassoon and Piccolo. Interestingly, the genetic ablation of both Bassoon and Piccolo leads to the deregulation of proteasomal activity in the presynapse, which eventually causes the loss of synaptic vesicles and progressive synapse degeneration (Waites et al., 2013). Our work here focuses on the understanding of the UPS role in the regulation of different forms of presynaptic plasticity but also the mechanisms controlling the UPS activity during these processes.


Regulation of presynaptic function by amyloid beta

Maria Andres-Alonso, Vesna Lazarevic

Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder leading to cognitive decline and dementia. At the cellular level AD is characterized by a progressive loss of synapses and subsequently nerve cells, which is causally linked to excessive amounts of amyloid-β protein (Aβ), a cleavage product of transmembranal amyloid precursor protein (APP). There is strong evidence that Aβ oligomers inhibit synaptic transmission by postsynaptic mechanisms and exert neurotoxicity leading to spine retraction, which finally results in loss of synaptic contacts. Recently, it has been reported that at normal physiological concentrations Aβ positively regulates synaptic transmission by modulation of neurotransmitter release from the presynapse (Abramov et al., 2009). This presynaptic regulation occurs at concentrations of Aβ, which are thousand-fold lower compared to concentrations of oligomers causing postsynaptic inhibition (Puzzo et al., 2008). Thus, dysregulation of presynaptic function induced by subtle imbalance of Aβ metabolism might represent the primary event in AD pathology and underlie the early cognitive deficits observed in AD patients long before the loss of neurons is detected. In our work we investigate the molecular and cellular mechanisms underlying the Aβ-induced modulation of presynaptic function and its relevance during experience-induced and homeostatic synaptic plasticity.


Molecular and cellular mechanisms of antidepressant action of ketamine

Franziska Altmüller (IHG, OVGU), Santosh Pothula

One-time application of subanesthetic dosis of ketamine, a NMDA-receptor antagonist, has long-lasting antidepressant action in patients and animal models, and induces reversal of behavioral, morphological and functional neuronal abnormalities. However, the principles of ketamine action at cellular and molecular level are not fully understood. We hypothesize that single dosis of ketamine application induces neuronal plasticity that leads to reconfiguration of functional brain connectivity. To test this hypothesis we investigate immediate and prolonged effects of ketamine on cellular signaling, gene expression, synaptic transmission and network connectivity. We work on this multidisciplinary project, funded by CBBS Magdeburg, together with our colleagues from the Institute of Human Genetics and CANLAB, OVGU and from the Neuroplasticity research group at LIN.


Presynapse-to-nucleus signaling via CtBP1

Daniela Ivanova, Anika Dirks (AG Chemical synapse, NCh)

Reconfiguration of gene expression patters is required to convert the rapid activity-induced changes of synaptic efficacy in persistent alterations in circuit performance. However, it is not well understood, how synaptic activity - in particular presynaptic performance - is coupled to gene expression in nucleus. In our recent work we have shown that CtBP1, a transcriptional co-repressor enriched in presynapses and nuclei, shuttles between these two locations and functions as molecular messenger linking presynaptic activity and activity-driven reconfiguration of neuronal gene expression (Hübler et al., 2012; Ivanova et al., 2015). CtBP1 is anchored to presynapse through a direct interaction with presynaptic scaffolds Bassoon and Piccolo, which is regulated by neuronal activity via modulation of NAD/NADH levels. Once CtBP1 dissociates from its presynaptic anchor it translocate to nucleus becomes available for nuclear import and functions as transcriptional co-repressor. Thus, CtBP1-mediated presynapse to nucleus signaling couples molecular rearrangements in presynapse with the reconfiguration of neuronal gene expression. In our future work, we want to identify the physiological signals inducing shuttling of CtBP1, the presynaptic signaling cascades involved in the modulation of synaptic retention of CtBP1, the mechanisms of its retrograde trafficking and regulation of its nuclear import and export. CtBP1 is one the very few presynapse-to-nucleus messenger proteins described to date and might play an important role in the integration of dendritic and axonal signals resulting in specific regulation of gene expression dependently on activity of entire brain circuits.

In highly active neurons NADH abundance increases which leads to synaptic enrichment of CtBP1 due to a tighter association with its presynaptic anchor Bassoon/Piccolo. CtBP1-mediated transcriptional repression of activity-dependent genes is released. In conditions of low activity or low NADH levels, CtBP1 dissociates from Bassoon/Piccolo, becomes available for nuclear import and transcriptional repression. (Ivanova et al., 2015)




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