Illumination of Cortical Circuit Dynamics

T. Knöpfel^1,2

¹ Laboratory of Neuronal Circuit Dynamics, Department of Medicine,

Imperial College London, UK

² Centre for Neurotechnology, Imperial College London, UK

Historically, advances in neuroscience have often been initialized by novel enabling technologies. A major current goal of neuroscience is to understand the neural substrates of cognition and to unravel the underpinnings of brain disorders. The technological challenge associated with this goal is to develop a methodology for dissection of neural circuits and their functions underlying behaviour. Optogenetics - the use of light and genetics to manipulate and monitor the activities of defined cell populations - has provided powerful tools that meet this challenge. The optogenetic toolbox has two compartments: tools for controlling and tools for monitoring neuronal activities. After a brief introduction of both types of tools, I will focus on experimental approaches to map cortical activities in behaving rodents via optical imaging using genetically encoded voltage and calcium indicators (GEVIs and GECIs). After reviewing the development of GEVIs, the presentation will focus on current GEVI applications. Finally, I will discuss expectations raised by the combination of optogenetic control and optogenetic monitoring, known as all-optical electrophysiology.

Acknowledgments: Work of my laboratory is supported by grants from the BRAIN Initiative, National Institutes of Health (NIH, U01MH109091, 1U01NS099573).

Understanding the biology of Alzheimer’s disease - Insights for development of therapeutics

Nancy Y. Ip

Division of Life Science and State Key Laboratory of Molecular Neuroscience,

The Hong Kong University of Science and Technology, Hong Kong, China

Alzheimer’s disease (AD), a leading cause of mortality in the elderly, is characterized by memory loss and impaired reasoning. The pathological hallmarks include the accumulation of amyloid plaques composed of beta-amyloid (Aβ) protein and neurofibrillary tangles in the brain. Since past drug development efforts targeting the Aβ pathway have met with limited success, there is an urgency to develop alternate therapeutic strategies. My lab is focused on investigating the pathological mechanisms underlying AD, including the dysfunctions in synaptic plasticity and innate immunity. Recent findings have unveiled exciting discoveries and identified new molecular targets associated with the disease, and we are examining the possibilities of developing alternative strategies. In this seminar, I will present our exciting work that led to the identification of two cell surface receptors as potential drug targets for AD.

My team and I first determined the role of a receptor tyrosine kinase EphA4, a negative regulator of synaptic plasticity in the brain, in mediating synaptic dysfunctions in AD. We found that EphA4 is overactivated in the postsynaptic hippocampus of a AD transgenic mouse model, which leads to the impairment of synaptic plasticity in these mice. Small molecule EphA4 inhibitors were subsequently identified, and their ability to alleviate impaired synaptic plasticity and pathology in AD was demonstrated, resulting in the discovery of a potential therapeutic strategy for AD. Meanwhile, innate immunity has emerged to be an important mediator of the pathogenesis of AD, and our recent work has shown that impaired signaling of interleukin-33 (IL-33) and its receptor ST2 is associated with the progression of the disease. Importantly, injection of IL-33 into an AD transgenic mouse model rescued synaptic dysfunctions and contextual memory deficits. Moreover, the beneficial actions of IL-33 were found to be mediated by regulating the activation state of microglia, specifically enhancing their β-amyloid phagocytic capacity and reducing their proinflammatory response in the brain. Taken together, our work highlights the importance of cell surface receptors as drug targets for the development of therapeutic interventions for neurodegenerative diseases, and has opened up new opportunities in AD drug discovery and development.