Silvia Viana da Silva: Hippocampal circuits underlying spatial memory deficits in Alzheimer’s disease

Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)

Alzheimer’s disease (AD) is characterized by a striking loss of memory. The hippocampal (HP) formation, severely affected in AD patients, is central to mnemonic processes. To gain insights into memory formation and its breakdown in diseases, we need to advance our understanding about the role of distinct HP regions in the creation and retrieval of memories. Expressing proteins found in familial forms of AD causes a wide range of synaptic deficits in mice, yet it is not well understood how these synaptic deficits change the network to cause memory impairment. To address this knowledge gap we used a new transgenic mouse line expressing human amyloid precursor protein (APP) selectively in CA3 pyramidal cells. This allowed us to dissect how AD associated synaptic deficits affect a pathway that is considered critical for supporting episodic memory. Unlike earlier studies using pan-neuronal disruptions or total silencing of cell populations, a key aspect of our model is that it provides a selective approach in which only HP synaptic function is affected. We recorded spatial and temporal properties of neurons as well as HP oscillations in freely moving mice while they performed a HP-dependent spatial navigation task. Despite the restricted APP expression, we found a robust impairment in the performance of CA3-APP mice and a reduction of the theta and gamma oscillation frequencies. Surprisingly, the spatial properties of place cells in CA1 and DG/CA3 regions remained mostly unaltered. Rather, we found that ~20% of principal cells have disrupted temporal dynamics in all subregions. Specifically, a subpopulation of principal cells had a lower intrinsic frequency, and the relationship between cells and the ongoing theta oscillations was also impaired, which is evident as a reduced phase precession in CA1 place cells. Interneurons were not directly manipulated but nonetheless displayed changes in their temporal firing properties. By testing mice at two age points we were able to determine that the reduced network frequency precedes the shift in the frequency of individual cells. These results provide the first evidence that even limited local AD pathology leads to widely altered network function, indicating that altered network mechanisms could contribute to trans-synaptic disease progression in addition to changes at the level of individual cells. In addition, our results further strengthen the idea that memory in AD could be improved by restoring brain oscillations.

 

Guests are welcome!

 

Organized by

BCCN Berlin / Margret Franke / Lisa Velenosi


Silvia is a new member of the BCCN Berlin.

Location: Virtual talk

Go back