Circuit and stage specific rules for activity in neuronal wiring

How does the brain wire up during development, and how does activity in the brain govern this process? Although this fundamental question has attracted a huge amount of investigation over many years, it remains controversial, with much data that appears conflicting. However, even within a given brain region, different and distinctive neurons make different and distinctive connections. In this proposal, we suggest that rather than a 'one size fits all' set of rules for wiring, different types of activity will operate at particular periods or 'time windows' during development in a circuit-specific way.

We will focus on a part of the brain called the hippocampus, which has long fascinated researchers due to its critical role in learning, memory and spatial navigation. During early development, before the onset of sensory experience, the brain generates its own 'activity'. Neurons release neurotransmitters, such as the excitatory transmitter glutamate, even before synapses (the connections between neurons) are formed. They also exhibit spontaneous firing, or voltage changes, often synchronised in groups. We will aim to identify which types of activity are important for the formation of synaptic connections and the shaping of the finely branched processes of the neuron, operating during which development stages, and see how this depends on the specific connection or circuit in the hippocampus. We will be able to use transgenic mouse lines and viral targeting to precisely control the timing and location of different types of activity blockade in developing hippocampal circuits. We will then be able to image neurons in 3D to assess the impact of these manipulations on their shape and the density of synapses formed onto them, as well as recording the electrical signals of these synapses.

Elucidating the specific rules that govern the formation of specific circuits will help us to understand how these circuits function in adulthood, and will be critical for improving how we investigate and develop new treatments for disorders of brain development.

In this proposal we address a fundamental question in neuroscience: the role of neuronal activity in governing how the brain wires up during development. This question has attracted a huge amount of investigation over many years, but much conflicting data and controversy has emerged. This suggests that a 'one size fits all' theory may not apply, but rather that there may be specific rules for specific circuits, potentially operating over different time windows during brain development. Our previous in vitro work in hippocampal neurons suggested that early spontaneous release of the excitatory neurotransmitter glutamate acts on postsynaptic NMDA receptors to drive synapse formation and dendritic arborisation. However, not only is there conflicting data from the literature on this issue, but we cannot address circuit specificity in vitro. To address where and when different types of activity play a role in circuit development, we need to be able to achieve precise temporal and spatial control over interventions that disrupt activity, in vivo. We are now able to achieve this goal using conditional (floxed) transgenic lines with mutations that interfere with different types of activity and either targeted viral delivery of Cre or specific, inducible Cre-expressing lines. We will use 3D imaging of neuronal and synaptic structure, with electrophysiological and electron microscopic validation, to assess the impact of these interventions. In this way, we will generate a road-map for the timing and circuit specific role of different types of activity in neuronal development.

Potential beneficiaries of this work include pharmaceutical companies, patients with neurodevelopmental disorders and their families, and the wider public.

This research proposal aims to understand fundamental mechanisms underlying the role of neuronal activity in the development of specific circuits and neuronal connections in the brain. This work will have important implications for research into the pathophysiology of neurodevelopmental disorders such as autism spectrum disorders, schizophrenia and intellectual disability, where synapse formation and function are widely believed to be disrupted. We believe that furthering our knowledge of physiology in these areas will lead to a greater understanding of pathogenesis and, in the longer term, eventually to new therapeutic approaches, with potentially significant benefit to the health and well-being of society. Should any results show potential for commercial exploitation, this would generate concurrent R&D investment and economic benefits to companies (possibly targeted for UK-based ones), collaborating research institutions and other involved sectors, as well as eventual use in clinical practice with obvious benefits to patients.

Through our efforts to increase knowledge about how the brain develops to children, families and in schools, we hope to inspire a new generation to contribute to the immense challenge of improving our understanding of brain function and the attempts to treat its pathology. Involvement with schools will have an additional beneficial societal impact. We can try and improve the understanding of neuroscience, and particularly the importance of researching basic questions, of the general public through public engagement schemes which could have indirect benefits for society in general.

Finally, staff working on the project would develop various potentially transferable skills such as computing/IT/programming abilities and innovative approaches to problem solving. In addition, the researcher will attend the Kings College London Researcher Development Program, which includes a choice of training courses on multiple transferable skills.