Axon signaling in hippocampal fast-spiking interneurons

The brain is an enormous network of neurons that connected by axons. Axons are long neuronal processes that carry information from the cell body to synapses where individual neurons communicate with each other. Thus, the axon works as the main output structure of a neuron, and knowledge of how information is processed in the axon is critical to understanding how the brain works. However, the small size of axons in the brain represents as a technical challenge for a detailed functional analysis. The cortical neuronal network consists of excitatory principal neurons and inhibitory interneurons. I will study the axon of inhibitory interneurons in the brain. As their name implies, these neurons inhibit other nerve cells. Thus, they regulate the excitability of the neuronal network, and their dysfunctions often cause epilepsy. Interneurons also have a central role in information processing in the brain. They coordinate how information, which is largely carried by the activity of excitatory neurons, flows within the neuronal network in space and time. To understand these functions, it is important to study the properties of interneuron axons. I will focus on the parvalbumin-expressing GABAergic basket cells, which represent one major type of inhibitory interneurons in the cortical network. These interneurons play a number of important roles in functions of the brain. Many of these functions depend on the fast signaling in the interneuron axons. The goal of this project is to unravel the mechanism underlying this remarkably rapid signaling in the interneuron axon with a combination of advanced electrophysiological, imaging techniques and computer modeling methods. The proposed research plan will expand our knowledge of the design logic behind the fast information processing in the nervous system. Furthermore, our data will provide important building blocks for constructing computer models of neuronal network in the brain. At the end of the project, we have discovered that the fast axonal signaling in interneurons is metabolically highly efficient. In addition, we have discovered a mechanism that allows the interneuron to maintain the speed of axonal signaling during high-frequency activities. These results, which have been published in the prestigious journal Neuron and Nature Communications, have far-reaching implications for understanding the relationship between brain metabolism and neural coding.

By targeting our analysis to the axon, which produces and transmits action potentials, we have demonstrated that action potential signaling in inhibitory interneurons is metabolically efficient (Hu et al. 2018, Neuron). This result has challenged the prevailing view that action potentials in interneurons are metabolically inefficient and have a high energy requirement (Carter and Bean, 2007, Neuron). Furthermore, we have demonstrated that axonal HCN channels ensure the fast and reliable coupling between action potential initiation in the proximal axon and Ca2+ entry in distal axon terminals during high-frequency firing. This result was published in another high impact factor journal (Nature Communications, impact factor: 14.9). This result may shed light on the subcellular mechanism underlying high order cognitive functions. Furthermore, this result has strong translation implications because HCN channel gene mutations are implicated in epilepsy and cognitive disorders.

Fast-spiking, parvalbumin-expressing GABAergic interneurons (basket cells, BCs) play a key role in cortical neuronal network functions. For example, these interneurons control the spike timing of principal neurons and contribute to the generation of network oscillations. Many of these functions depend on the rapid signaling in basket cell axons. In essence, basket cells are able to convert an action potential into the release of GABA within less than one millisecond. However, the functional properties of basket cell axons are poorly understood. The goal of this proposed research plan is to examine the axon signaling of hippocampal basket cells in brain slices. Towards this goal, we will use a combination of advanced subcellular patch-clamp methods, imaging techniques and theoretical modelling. Specifically, we will investigate the energy efficiency of the fast action potential initiation and propagation in basket cell axons, and we will seek the factors determining the timing and efficacy of action potential-dependent calcium entry that triggers synaptic transmission in basket cell presynaptic terminals. The proposed research plan has important implications for understanding the contribution of interneurons to cortical processing and brain energetics. Through close national and international collaboration, the project will combine the expertise of several research groups within and outside the University of Oslo, and also includes the transfer of the expertise from a world leading neurophysiology group in Austria.