Much of the neuronal damage that occurs during seizures, in stroke and traumatic brain injury is due to excessive extracellular levels of glutamate. The release mechanisms for glutamate are located mostly in boutons on very thin, unmyelinated axons. We know that these grey matter axons (GMAs) release glutamate when depolarized, either by action potentials, by pathological increase in extracellular K+, or by energy deficiency as in stroke, but very little is known about the channels involved, and how they control the membrane potential, including the action potential ('spike'). This lack of knowledge about the electrical events that control GMA function prevents development of treatments aimed at controlling excessive glutamate release. Our goal is to identify mechanisms in GMAs that control the repolarization of the spikes, including their after-potentials, and understand how these mechanisms operate in normal and pathological GMA function. To achieve this we will use a set of electrophysiological tools on hippocampal and cerebellar slices. These include single axon and single neuron recording techniques, excitability testing, and a new, modified grease-gap technique that allows recording of the shape of the GMA spike. Using this repertoire of axon-specific techniques we recently showed that the spike in hippocampal Schaffer collaterals and cerebellar parallel fibers has a depolarizing after-potential, which can explain the hyper-excitability and bursting that sometimes follows individual spikes in these thin axons. These experiments will identify mechanisms in GMAs that control the excitability, and particularly the repolarization of the spike, which is tightly linked to the release probability of glutamate. The experiments may also establish GMAs as potential sites for loss of proper excitability control and help target specifically the mechanisms that control spikes and their after-potentials. This would give alternative drug targets for therapies that often fail, for exampe in stroke, and in 30% of all epilepsies.
Glutamate is the most common neurotransmitter in human brain, but it is toxic if it occurs in too high concentration, as during seizures, stroke and traumtic brain injury. We will investigate the electrical events that influence glutamate release to help th development of treatments that can better protect our brain from such glutamate toxicity.
|Pekala, Dobromila; Baginskas, Armantas; Szkudlarek, Hanna J et al. (2014) Components of action potential repolarization in cerebellar parallel fibres. J Physiol 592:4911-29|