A study by researchers from the MRC Centre for Developmental Neurobiology (CDN) at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) reveals a new way by which neurons alter their structure in response to changes in their electrical activity. The results have been published in the Journal of Neuroscience.
In the developing nervous system neurons must migrate, mature and connect with each other to produce functional networks. However, they do not do so in a vacuum – as brain development proceeds, its cells need to adapt to constant disturbances caused by changes both in the external environment and in their own internal milieu. Failure to do so can result in debilitating neurodevelopmental disorders such as epilepsy, schizophrenia or autism. Fortunately neurons are known to have a wide range of mechanisms, collectively known as ‘plasticity’, for adapting in response to ongoing changes in their electrical activity.
One such mechanism, first uncovered by work in the MRC CDN in 2010 (Grubb & Burrone Nature 365:1070), involves alterations in the specialist machinery inside a neuron that generates electrical signals known as action potentials. This machinery is concentrated in a part of the cell known as the ‘axon initial segment’, or ‘AIS’ for short. Any alterations of the AIS can impact significantly on a neuron’s electrical output, with knock-on effects on the surrounding network. However, all previous work has focused on AIS plasticity in excitatory neurons, which act as an ‘on’ switch in neuronal networks.
This study is the first to investigate AIS plasticity in inhibitory neurons, which are the equivalent of a brain circuit ‘off’ switch.
Senior author Dr Matthew Grubb from the MRC CDN, said: ‘We’ve known for a while that the AIS is a changeable part of the neuron, but that’s only ever been shown for excitatory cells. This study provides the first evidence that the AISs of inhibitory neurons can be plastic too.’
The research centred on a unique population of neurons in an area of the brain that controls our sense of smell: the olfactory bulb. These cells produce the neurotransmitter dopamine, and have an inhibitory (‘off’) function within their local circuits. They are also known to be highly plastic, changing in numerous ways in response to perturbations in olfactory experience. This study, however, was the first to identify AIS plasticity in this cell type. By increasing levels of electrical activity in olfactory bulb neurons grown in cell culture, Dr Grubb’s team found that the AIS of dopaminergic cells underwent two important changes: it relocated to a position that was closer to the cell body, and it grew longer. These changes could be reversed if the stimulus was taken away, providing new evidence of the ability for the AIS to change ‘bidirectionally’ in an activity-dependent manner.
Dr Grubb added: ‘Excitatory and inhibitory neurons perform largely opposing functions within neuronal circuits, so it might be expected that their responses to activity perturbations could also push in opposite directions. This is what we found here: the AIS plasticity we observed in inhibitory dopaminergic neurons was an inverted, mirror image version of the plasticity we observed in excitatory cell types. This diversity may be important for neuronal networks as a whole to be able to adapt to long-term alterations in their input.’
This work was supported by a Wellcome Trust Career Development Fellowship (M.S.G.) and a Wellcome Trust Sir Henry Wellcome Fellowship (E.G.).
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Paper reference: Chand, A. N., Galliano, E., Chesters, R. A. & Grubb, M. S. ‘A distinct subtype of dopaminergic interneuron displays inverted structural plasticity at the axon initial segment’ Published in Journal of Neuroscience 28 Jan 2015. 35, 4, p. 1573-1590. DOI: 10.1523/JNEUROSCI.3515-14.2015.