Real brains in real time; the power of electrophysiology

In both patients and rodent models we see the same structural changes in neuronal circuitry across the brain.

If neuronal cells do not form the appropriate synaptic contacts then our ability to learn, remember, and perceive the world can be detrimentally altered.

Through our collaboration on DEFINE, we have generated rodent models which have key genetic mutations associated with neuropsychiatric disorders, and using electrophysiology we can study synaptic connectivity in real time at the single cell resolution.

Background

The underlying genetic architecture for schizophrenia and associated conditions is complex. The disorder comprises genetic mutations conferring high risk, and those genetic mutations conferring low risk. Therefore, understanding the function of high risk genes presents an optimum method for advancing our understanding of these conditions.

Despite the complexity of the disorders, some coherent pathways, associated with genetic risk factors, are beginning to emerge; particularly in relation to synaptic function, and connectivity. Of interest to us are CYFIP1, CACNA1C, NRXN1, and DLG2. These genes are clearly associated with disease, but their synaptic function and role in disease require further study. Using in vivo and in vitro electrophysiology, our collaboration will attempt to bridge our understanding between genetic mutation and synaptic function.

Research

Our DEFINE collaboration comprises both in vitro and in vivo elements. Work performed by Dr Adam Ranson, utilises in vivo electrophysiology.

With this methodology we can look at real-time electrical activity in a network of cells, whilst the rodent performs a behavioural task. The method is very flexible, and allows us to study deficits in numerous behavioural tasks across multiple brain regions. On the in vitro side I can take brain slices, of key brain regions implicated in disease, and look at the electrical activity of single cells in real time. I also use quad-patch recording to study synaptic connectivity and activity in four cells simultaneously; across multiple cortical levels (figure 1).

Using optogenetics, I can use light-driven stimulation to study synaptic inputs from defined brain regions. The work of Dr Adam Errington, allows us to also record electrical activity from sub-compartments of a single cell: the dendrites (figure 2).

These are the regions of the cell which receive incoming electrical activity. Using two-photon glutamate uncaging, we can study how genetic mutations alter spatial-temporal summation of incoming information, and how this electrical activity is transferred from the dendrites to the cell soma.

Proposed outcome

The combination of these electrophysiological methods will provide a comprehensive picture of neuronal function; being able to study synaptic functions, synaptic proteins, receptor activity, and signal transduction pathways. A clear understanding of the pathways and receptors affected by single gene mutations, may allow us to find points of genetic convergence. If we observe multiple gene mutations to impact a particular pathway or set of receptors, then this will help guide more targeted, and therefore, effective treatments.

Leads