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Role of hemi-channels in the modulation of cortical microcircuits

Principal Supervisor: Dr Mark Wall, School of Life Sciences

Co-supervisor: Nicholas Dale and Magnus Richardson

PhD project title: Role of hemi-channels in the modulation of cortical microcircuits

University of Registration: University of Warwick

Project outline:

The neocortex is part of the brain that is involved in motor control, sensory integration and is the seat of consciousness. Correct function of the neocortex throughout life is vital for full cognition and can be compromised in neurodegenerative disease. The neocortex is a layered structure containing networks of pyramidal cells and inhibitory interneurons. The recurrent connections between these neurons allows the cortex to generate different patterns of activity which ranges from slow ripples, up-down states to epileptic activity. The activity of cortical circuits is not only dependent on the fast synaptic connections but is also controlled by neuromodulators such as adenosine and dopamine. In recent experiments we have discovered that hemi-channels are expressed by a subset of cortical neurons and these may also play a role in controlling circuit function. Hemi-channels are transmembrane proteins that comprise six connexin or pannexin subunits arranged around a central pore. The opening of these channels can be modulated by several stimuli, including transjunctional voltage, low pH, carbon dioxide and nitric oxide. There are many different connexins and pannexins which can produce homomeric and heteromeric hemi channels with different properties. The opening of hemi-channels can have several effects on neuronal function such as reducing the input resistance thus making neurons less excitable and less likely to fire. The opening of hemi-channels also allows the secretion of signaling molecules such as ATP which can also modulate neuronal and glial function. One way to study hemi-channels is to use dye loading, where fluorescent dyes are taken up by neurons when hemi-channels open and then the neurons can be visualized. From such experiments it was found that a subset of cortical neurons express hemi-channels. Interestingly the opening of these hemi-channels was modulated by the gaseous neurotransmitter nitric oxide (NO). This of particular interest as it is well established that NO production makes a key contribution to daily homeostatic sleep (slow-wave sleep, SWS; rapid eye movement sleep, REM sleep). Thus the hemi-channels may change circuit function which may play a role in the transition between sleep and wakefulness

Project objectives

  1. Identify the neuronal subtype that expresses hemi-channels and determine whether they are in all areas of the neocortex or instead have a restricted distribution.
  2. Determine the effect that hemi-channel opening has on neuronal and synaptic integration using electrophysiology and computational modelling
  3. Investigate the actions of nitric oxide and nitric oxide scavengers on hemi-channel opening and neuronal properties
  4. Determine how modulation of hemi-channel function changes patterned cortical network properties and changes sleep states 

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Production of viable cortical slices
  • Multiple whole cell patch clamp recording from upto 4 neurons
  • Whole cell patch clamp recording from soma and dendrites
  • Dye loading
  • Immunohistochemistry and confocal microscopy
  • Computational modelling and analysis
Contact: Dr Mark Wall, University of Warwick