DFG Graduiertenschule 2413 SynAge Teilprojekt 11: Impact of stress on aging of BDNF-dependent synaptic and cognitive functions

Während des Alterungsprozesses trage vielfältige biologische Prozesse und Umwelteinflüsse zum funktionalen Abbau der Leistungsfähigkeit von neuronalen Schaltkreisen des Gehirns bei. In diesem Zusammenhang sind stressreiche Ereignisse in der frühen Entwicklung sehr wahrscheinlich von besonderer Bedeutung. In diesem Projekt untersuchen wir in Mäusen, inwiefern Stress in frühen Phasen der postnatalen Entwicklung die synaptische Plastizität und das Lernverhalten im alten Organismus beeinflussen. Ein besonderer Fokus liegt dabei auf BDNF-abhängigen Mechanismen des Lernens und der synaptischen Plastizität.

Impact of stress on aging of BDNF-dependent synaptic and cognitive functions

During aging many biological and environmental processes contribute to the functional
decline of cells. However, the mechanisms how this aging is reflected on the level of altered
synaptic plasticity is unknown. Interestingly, there is a wide heterogeneity in the pace of
aging in human and animal populations (Foebel, Pedersen, 2016). One factor that likely
contributes to accelerated aging processes is the exposure to adverse environmental events
in early and/or later life (Gassen et al., 2017). There is strong evidence that stress-induced
3 Research Program RTG SynAGE
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Figure 12: A: Heterozygous BDNF knockout animals exhibit an age-dependent deficit in spatial learning. B: The
abundance of signaling-competent TrkB receptors declines with aging. C: BDNF protein expression declines in
different areas with aging.
alterations in BDNF expression contribute to long-lasting cellular and functional alterations in
the hippocampal network (Bath et al., 2013). Stressful events alter spine densities in areas
CA3 and CA1 of the hippocampus (Duman and Duman, 2015) and result in long-lasting
reductions in BDNF protein expression (Lakshminarasimhan and Chattarji, 2012). Since
BDNF is a key mediator of synaptic plasticity and exerts neuroprotective functions, reduced
BDNF levels and subsequently altered activation of downstream signaling molecules (Panja
et al., 2014) might be a key mechanism for accelerated aging of synaptic transmission. We
recently observed a decline of brain BDNF levels and abundance of signaling-competent
flTrkB receptors in aged WT mice (Petzold et al., 2015). In BDNF+/- mice this additional agedependent
decline leads to deficits in hippocampus- and amygdala-dependent learning
processes (Psotta et al., 2013; Endes and Lessmann, 2012; see Figure 12).
However, the mechanisms how BDNF and its downstream signaling molecules are involved
in these processes are widely unknown, thus limiting the exploitation of its possible therapeutic
potential against such aging processes. Identifying altered signaling events and protein
interaction partners downstream of TrkB activation are likely to provide novel approaches to
reverse stress-induced changes that result in accelerated aging.