Get excited: slowly and one step at a time

Get excited: slowly and one step at a time

Neurons in the hypothalamus can sum synaptic inputs over long time scales thanks to near-perfect synaptic integration by a voltage-gated sodium channel.

These findings, published recently in the journal Cell, provide valuable insights into how the brain sets long-term homeostatic functions like weight balance.

Generally, neurons are excellent at computing inputs over millisecond timescales. Neuronal cell types often integrate thousands of inputs, with fast decay times (frequently less than 20 ms), to process rapidly changing circumstances.

However, when it comes to phenomena like appetite and hunger, these circuits need to be able to sustain activity over a period of minutes, or even hours, to provide the motivation to drive feeding behaviours.

A collaborative research project from the laboratories of Dr. Scott Sternson and Dr. Tiago Branco showed that in the hypothalamus, neurons that regulate body weight (AGRP, POMC and PVH neurons) can achieve sustained activity using a fundamentally different mode of synaptic integration than many others.

They demonstrated, in acute slice experiments, that the voltage-gated sodium channel Nav1.7 prolonged the extracellular postsynaptic potentials (EPSPs) of these cells via a persistent sodium current. Furthermore, in vivo experiments of PVH neurons showed they could amplify synaptic inputs with near-perfect integration.

Knocking-out Nav1.7 selectively in mice reduced EPSP duration in AGRP and POMC neurons and had profound effects on the animals’ weight. The deletion of Nav1.7 in AGRP neurons led to a loss of near-perfect integration and a loss in body weight. The same deletion in POMC neurons led to weight gain.

No pain, some (weight) gain?

People who lack functional Nav1.7 are unable to feel pain, and so this ion channel subunit is an attractive target for the development of analgesic compounds. However, these findings suggest there may be potential side-effects for appetite and weight maintenance. Since the neurons involved have differing effects on appetite regulation, it is not clear what the consequences of a complete block of Nav1.7 would be.

Additionally, further work on these neurons and the effect of Nav1.7 on weight may lead to novel therapies for those suffering from obesity or eating disorders.

Further studies on the integration of inputs in different neuronal cell types may expand our understanding of the computational schemes used by the brain.

Dr Tiago Branco and Dr Adam Tozer discuss their recent Cell paper

Dr Tiago Branco

Dr Branco’s lab, now at the Sainsbury Wellcome Centre for Neural Circuits & Behaviour at UCL, currently works on the biophysical mechanisms through which animals compute instinctive decisions. They investigate how neurons generate activity patterns to allow an animal to engage in one behaviour versus another e.g. how do animals decide whether to between escaping from a potentially dangerous situation in the presence of food or trying to get the food instead of escaping.

The experiments discussed in this paper were conducted at the MRC Laboratory of Molecular Biology in Cambridge, UK.

Slice electrophysiology recordings

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​Paper reference

Branco T., Tozer A., Magnus C. J., Sugino K., Tanaka S., Lee A. K., Wood J. N., Sternson S. M. Near-Perfect Synaptic Integration by Nav1.7 in Hypothalamic Neurons Regulates Body Weight Cell (2016) doi: 10.1016/j.cell.2016.05.019

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