Person:

Lutas, Andrew

Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing 'leak' current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual mouse SNr neurons. We discovered that SNr neurons express the sodium leak channel, NALCN, and that SNr neurons lacking NALCN have impaired spontaneous firing. In addition, NALCN is involved in the modulation of excitability by changes in glycolysis and by activation of muscarinic acetylcholine receptors. Our findings suggest that disruption of NALCN could impair the basal ganglia circuit, which may underlie the severe motor deficits in humans carrying mutations in NALCN. DOI: http://dx.doi.org/10.7554/eLife.15271.001

Epilepsy is a common neurological disorder, affecting around 1% of the world’s population. For many, drugs are available that can prevent their seizures. However, for close to one third of those who suffer from epilepsy, current medicines simply do not work. Surprisingly, a change in diet can dramatically stop seizures when medications cannot. This diet, known as the ketogenic diet, involves switching from a typical western diet of high carbohydrate content to one of almost entirely fats, which induces a state of ketosis or elevated circulating ketone bodies. The liver generates these ketone bodies from fat to be used by other tissues in the body as a fuel. In particular, during ketosis, the brain begins to utilize ketone bodies in addition to the usual fuel, glucose. The ketogenic diet is very effective at preventing seizures, but remains poorly understood. How might a change in fuel utilization in the brain have such a profound impact on epilepsy? One of the best known links between cellular metabolism and excitability is the ATP-sensitive potassium (KATP) channel. When the intracellular ratio of [ATP]:[ADP] decreases sufficiently, these channels open to generate a hyperpolarizing effect on cells. In the brain, this activity of the channel can limit the spiking of neurons. Remarkably, we have found that the presence of ketone bodies can also favor the openings of these channels providing a hypothesis for how the ketogenic diet might act to prevent seizures. Yet, the mechanism for how changes in fuel metabolism in brain cells leads to increased KATP channel opening is not known. This thesis presents work aimed at understanding whether decreases in glucose metabolism in neurons is capable of activating KATP channels to affect neuronal firing. We find that, while disruption of glucose metabolism can activate KATP channels, it requires that mitochondrial ATP production is lowered. In addition, disrupting glucose metabolism can also affect a nonselective cation current in spontaneously active neurons, leading to a slowing of firing. Together, these findings provide new understanding of metabolic conditions in neurons that modulate ion channel activity and ultimately neuronal excitability.