The aims of the project is to define nerve cell types (neurons), synaptic plasticity, consisting of neuron-to-neuron change of communication strength, and effects induced by key neuroactive drugs in slices of living human cerebral cortex.
Although brain diseases are very widespread, discoveries of new therapies are developing slowly. A crucial factor hampering progress is the lack of good animal models for human brain diseases leading to failure in clinical translation. Furthermore, neuronal centres of the human brain consist of many distinct cell types, but our knowledge on their identity, responses to drugs and roles in the neuronal circuits is still very limited. Cell-type specific therapies may fail if heterogeneity of structure and function across species is neglected.
Our programme aims to improve this situation. We use surgically resected human cortical tissue that is normally removed and discarded in order to gain access to deeper brain areas during neurosurgery. We obtain small cortical samples and keep them alive as oxygenated thin slices of for several hours. This allows us to investigate the physiological interactions and roles of specific neuron types, their synaptic plasticity and their responses to neuroactive drugs. The experiments consist of electrophysiological recordings, involving the detection if voltage potentials of few millivolts or the detection of picoampere magnitude membrane currents, by insertion of a thin recording device into each neuron, from one to three neurons at the same time. We investigate synaptic plasticity and the effects mediated by clinically relevant pharmacological agents (e.g. cognitive enhancers). After the electrophysiological recordings, the slices containing the recorded cells, are fixed, re-sectioned and subjected to immunohistochemical reactions to identify key molecules expressed by specific neuron types. Using this approach, the programme provides exciting discoveries on human cortical neurons that use gamma-butyric-acid (GABA) as a molecule in their synaptic communication and pharmacological responses.
The results have demonstrated the value to define neuronal cell types, synaptic interactions and drug sensitive sites in the human neocortex, which is based on the in vitro recording of a sample of uniquely diverse GABAergic neurons and pyramidal cells at Oxford and Aarhus. Many molecularly defined neuronal types were recorded for the first time.
