Subunit specific mechanisms by which potassium channels mediate intrinsic plasticity and neuronal integration in the auditory pathway

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The brain receives signals from sense organs (such as the ear) and processes it to extract information about the world. The incoming signals are in the form of electric pulses called 'action potentials' (APs). They are around 0.1 Volts in amplitude and 1 millisecond in duration. The APs propagate along nerves to release chemical messengers between brain cells (neurons) at specialized connections known as synapses. Much of this signalling is done by proteins called ion channels. These proteins are built from subunits each specified by a gene. Neurons must assemble all these proteins into molecular machines for signalling. My lab focusses on one class of voltage-gated ion channels called "potassium channels", for which there are over 80 genes. These potassium channels are the foundation on which all other forms of excitability are built, and they help to dampen the excitability after one signal, so that neurone is ready for the next.The mechanism(s) by which the neurons control their potassium channels are fundamental for brain function and consciousness: too little activity of potassium channels and the brain goes epileptic, too much and we are become catatonic. This grant will explore the mechanisms by which two families of potassium channels are regulated (a voltage-gated family called Kv3 of which there are four members (Kv3.1-3.4) and a family of leak (or flux-gated) potassium channels called two-pore or K2P channels.Most studies of potassium channels are done in cell lines, but to understand their function, studies must be conducted in real neurons within an actual brain; hence we work in vitro, on tissue from the brains of humanely killed mice. These ion channels are nearly identical to those of humans. We can measure the brain activity and manipulate the potassium channels to test their contribution to specific tasks.Our model system for this study is hearing and the brain. This is because listening requires fast processing and extreme precision in integrating information from both ears, so as to map sound objects and identify external threats (the sound of a car) or extract information from noisy environments (listening to a conversation in a bar). My laboratory has extensive experience of channel and auditory science.There are over 80 genes for potassium channel subunits, so we work on a subset of 4 genes in a family known as Kv3 (potassium channel family three). Crucially, only two of these genes are expressed in the auditory brainstem, and we have transgenic knockout mice for both genes. We are most interested in the third gene of the Kv3 family (Kv3.3) as mutations of this gene are linked to hearing disorders. We aim to discover why these channel subunits are so crucial for sound processing and to understand how mutations can produce disease. A mutation in Kv3.3 also causes a form of neurodegeneration in the cerebellum called spinocerebellar ataxia 13 (SCA13), so we anticipate that our basic science results will help understand mechanisms of hearing and also be important for understanding age-related hearing loss, which may in turn be relevant to understanding why neurons die in dementia.