Cycle 4 project 1

Plasticity of local CA3 circuits in mouse models of Alzheimer’s disease: involvement of epigenetic mechanisms

 

Pei-ZhangPhD student: Pei Zhang, China
Home Institute: Bordeaux Neurocampus; Principle Investigator: Christophe Mulle
Host Institute: European Neuroscience Institute Göttingen; Principle Investigator: Fischer, André

Executive Summary

In the early stages of Alzheimer’s disease (AD), there is a strong correlation between memory impairment and cortical levels of soluble amyloid-ß peptide oligomers (Aßo). Elevated levels of Aßo disrupt glutamatergic synaptic function, which in turn may lead to the characteristic cognitive deficits. Experiments in rodents have conforted the notion that Aßo impair synaptic transmission and plasticity, and that mouse models with increased production of these oligomers display cognitive impairment.

How Aßo impacts on reorganization of synaptic circuits following learning has not yet been addressed. In hippocampal CA3 region, mossy fibre terminals, at the entry of hippocampal circuits, rearrange upon encoding of new information in mice (Ruediger et al, 2011). It has thus been postulated that plasticity and feedforward inhibition growth at hippocampal mossy fibres relate to the precision of hippocampus-dependent memories. In the home lab, the PhD student will combine electrophysiological analysis of the activity of CA3 local circuits with behavioral experiments. More specifically, he/she will compare the properties of mossy fiber synaptic transmission and feedforward inhibition in CA3 pyramidal cells following contextual fear conditioning in wild-type and in APP/PS1 mice.

In addition, altered synaptic plasticity will be correlated with epigenetic changes in gene-expression and learning behavior in the host lab. De-regulated epigenetic gene-expression linked to histone-modifications, DNA-methylation and the action of non-coding RNAs contributes to the pathogenesis of AD and age-associated memory decline (Fischer et al, 2007) (Kilgore et al, 2010) (Govindarajan et al, 2011) (Peleg et al, 2010) (Fischer et al, 2010). Precisely, how the major risk factor for AD – elevated Aßo load – contributes to epigenetic change is not known. In close collaboration with the electrophysiological analysis and the outcome of the behavior data we will choose two time points for epigenetic profiling. (1) Before and (2) at the onset of synaptic and behavioral deficits in APP/PS1 mice. Specifically we will analyse the CA3 region and analyze gene-expression using paired-end RNA sequencing that will allow us to define the absolute expression of all mRNA, splice variants and long non-coding RNA species. This data will allow us to link specifc changes in epigenetic gene-expression to Aßo-mediated dysfunction in synaptic remodelling. Based on this data we will select at least two HDAC inhibitors with different specificity (e.g Ms-275 and Vorinostat) and subsequently analyze whether HDAC inhibition can restore synaptic plasticity at the mossy fiber-CA3 synapse.

The originality of the project is two-fold : 1) it will address the question of how learning-induced changes in synaptic structure and function are altered in an AD mouse model; 2) it will study how epigenetic mechanisms are involved in this synaptic remodelling process in the AD mouse model. This project is at the crossroad of the expertise of the two labs, in synaptic electrophysiology (in particular in CA3) (home lab), and in epigenetic mechanisms in the context of AD (host lab).

In conclusion we will obtain important information to further elucidate the question how Aßo impact on synaptic plasticity mechanisms related to learning and mediate cognitive decline.

References

Fischer A, Sananbenesi F, Mungenast A, Tsai LH (2010). Trends in Pharmacologicla Science 31: 605-617
Ruediger, S., Vittori, C., Bednarek, E., Genoud, C., Strata, P., Sacchetti, B., & Caroni, P. (2011). Nature, 473(7348), 514–518.
Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH (2007). Nature 447: 178-182
Govindarajan N, Agis-Balboa C, Walter J, Sananbenesi F, Fischer A (2011) Journal of Alzheimer’s Disease 24: 1-11
Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G (2010) Neuropsychopharmacology 35: 870-880
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Java S, Agis-Balboa RC, Cota P, Wittnam J, Gogul-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, KAng H, Farinelli L, Chen W, Fischer A (2010) Science 328: 753-756.

 

 

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