Restoring hippocampal-cortical circuit and memory dysfunction in prodromal Alzheimer's Disease.

Brains contain billions of specialised cells, called neurons, which are the fundamental building blocks of every circuit in the nervous system. The principal purpose of a neuron is to transmit information: when they receive sufficient input from other neurons, they send brief electrical pulses, called action potentials, which allows them to communicate with other neurons. Broadly speaking, neurons exist as two types: excitatory neurons, which make other neurons more likely to fire action potentials, and inhibitory interneurons, which make other neurons less likely to fire action potentials. If one were to compare the brain's electrical activity to music, then excitatory neurons provide the notes for the brain's 'music', whilst inhibitory interneurons provide the pauses between notes. All computations in the brain require very precise synchrony between different neurons: without the notes, there would be only silence, and without the pauses, the music would become a cacophony.

Recent research has shown that dementias, such as Alzheimer's Disease, cause a dysfunction in inhibitory interneurons. The resulting effects on normal brain function are severe and thought to translate to the cognitive and memory impairments seen in Alzheimer's Disease. Data from our labs shows that selectively manipulating inhibitory interneuron activity can restore normal brain function in mouse models of Alzheimer's Disease. Intriguingly, a similar rescuing effect has recently been attribute to non-invasive light and acoustic stimulation at frequencies similar to the frame rate of video (40 Hz).

Our project has two aims. One is of a basic science nature: We would like to determine the mechanisms underlying the rescue effects following stimulation of inhibitory interneurons and delivery of light and acoustic stimuli in mouse models of Alzheimer's Disease. The other aim is of a translational nature: We would like to see whether stimulation of inhibitory interneurons and delivery of light and acoustic stimuli in mouse models of Alzheimer's Disease can actually restore memory function in the early stages of Alzheimer's Disease.

Cortical and hippocampal neurons exist as two broad subtypes, excitatory glutamatergic neurons and inhibitory GABAergic neurons. Recent years have seen a huge leap in our understanding of their relative contribution to normal brain function. To address our project aims, we will employ two main experimental paradigms: (1) electrophysiology recordings in acute brain slices and in vivo of hippocampus and retrosplenial cortex and (2) behavioural assays. We will probe the role of somatostatin positive inhibitory interneurons (SST+) in neuronal oscillations both in control mice and mouse models of Alzheimer's Disease (AD, either through application of Abeta oligomers or in AppNL-G-F transgenic mice). We will use SST-Cre mice to deliver opsins to SST+ neurons only. Part of the project will require the generation of SST-Cre x AppNL-G-F mice to test the rescuing effect of SST+ stimulation in AD mice performing RSC-dependent memory tasks that are sensitive to prodromal AD dysfunction. A final set of experiments aims to explore possible links between the ameliorative effect of sensory stimulation on AD-associated deficits to the rescuing effect of SST+ stimulation.

We aim to generate impact threefold:

1. Academic Impact
The scientific benefits of this project include a better, quantitative understanding of the mechanisms underlying cognitive and memory impairments in AD. This understanding would feed into the development of potential novel therapeutic strategies. As such, the project will enhance our knowledge of both human and animal neurophysiology, and potentially open the door to new avenues of research within the UK and beyond.

2. Public Engagement
In addition to dissemination of knowledge through the usual scientific channels, we also aim to participate in public engagement activities. The lead applicant's lab (Kohl) is involved in a number of regular outreach activities with local high schools and at Science Fairs. A modest amount of impact costs on the grant will help us purchase and maintain a collection of materials and kit used in our outreach activities, such as backyard brains electrophysiology kits. The Kohl lab also hosts local A-level students in the summer as part of a widening participation programme, to learn basic immunohistochemistry and molecular methods. If funded, this project will certainly contribute to this in future years.

3. Economic and Social Impact
While it is hard to look into the future and predict what wider impact the basic science part of the project can have on society and the economy, we can anticipate some avenues through which our project may gain wider impact. Should SST+ activation and/or non-invasive sensory stimulation aid in rescuing AD-associated impairments, the impact would be significant. Stakeholders in the clinic and industry would likely take strong interest in the findings which could lead to novel treatment strategies for AD. Our project is an example of knowledge-driven development of new treatments for neuropathologies, based on an understanding of affected neuronal circuits. It would lead to economic impact for the pharmaceutical company developing the treatments, and to social impact through improvements in quality of life for those affected and their families.