By discovering a brain protein that ensures signals sent along nerve fibres don’t break down, researchers at the University of Edinburgh in the UK have found a new clue for understanding conditions like epilepsy, dementia, multiple sclerosis, stroke and other neurological disorders that occur when the brain can’t send signals to other parts of the body.
The study appears in the 10 March online issue of Neuron.
Co-author Dr Matthew Nolan, from Edinburgh University’s Centre for Integrative Physiology, told the press that the brain is constantly transmitting tens of thousands of messages along nerve fibres between cells in the brain and also to and from parts of the body.
“Identifying proteins that are critical for the precise initiation of these impulses will help unravel the complexities of how brains work and may lead to new insights into how brains evolved,” he explained.
Brain cells or neurons communicate with each other using electrical impulses. For these impulses to “make sense” and deliver precisely the correct message, given the wide diversity of functions that cells in the nervous system perform, they have to switch on and off at the right time, and have the correct voltage, amplitude and frequency, and maintain their signal strength from initiation to point of delivery.
Scientists already know that a section of the neuron called the axon initial segment (AIS), plays a crucial role in the generation and propagation of electrical nerve impulses or “action potentials” as they are termed.
They also know something about the structure of the AIS and how it is assembled, but not what keeps it stable, as Nolan and colleagues noted in their background information:
“Assembly of the AIS requires interactions between scaffolding molecules and voltage-gated sodium channels, but the molecular mechanisms that stabilize the AIS are poorly understood.”
Once generated in the AIS, the signal or electrical “spike” travels along the axon, which in the case of motor nerves can be as much as a metre long (for example to control a leg muscle).
To keep the integrity of the signal, a number of things have to happen, one of which is made possible by the presence of “nodes of Ranvier”, small uninsulated gaps between sections of myelin-encased axon.
Because they are uninsulated, the gaps, about 1 micrometer across, allow electricity to be generated: the structure of alternating uninsulated nodes and insulated sections is what maintains the speed and correct strength and pattern of the electrical impulse.
What Nolan and colleagues found was that the AIS and the nodes of Ranvier are assembled by distinct mechanisms, and that a neural form of a protein called Neurofascin, namely Nfasc186, stops the breakdown of the AIS and keeps it stable.
By knocking out the Neurofascin gene in the appropriate part of the brain in adult mice, the researchers caused rapid loss of Nfasc186 in the AIS but not in the nodes of Ranvier, leading to “AIS disintegration, impairment of motor learning and the abolition of the spontaneous tonic discharge typical of Purkinje cells”.
This last effect, the “abolition of the spontaneous tonic discharge typical of Purkinje cells”, describes a breakdown in the function of a type of cell that is essential for motor function, disorders of which usually affect movement.
Nolan and colleagues also showed that although loss of the Nfasc186 protein in the AIS did not stop action potentials from arising, it resulted in modified waveforms, so basic motor abilities remained intact.
They proposed that their findings show that “Nfasc186 optimizes communication between mature neurons by anchoring the key elements of the adult AIS complex”.
Senior author Professor Peter Brophy, Director of the University’s Centre for Neuroregeneration, said:
“Knowing more about how signals in the brain work will help us better understand neurodegenerative disorders and why, when these illnesses strike, the brain can no longer send signals to parts of the body.”
The Wellcome Trust and the Medical Research Council funded the research.
“A Critical Role for Neurofascin in Regulating Action Potential Initiation through Maintenance of the Axon Initial Segment.”
Barbara Zonta, Anne Desmazieres, Arianna Rinaldi, Steven Tait, Diane L. Sherman, Matthew F. Nolan, Peter J. Brophy.
DOI:10.1016/j.neuron.2011.02.021
Additional source: University of Edinburgh.
Written by: Catharine Paddock, PhD