Understanding How BK Potassium Channels Enhance a Neuron's Input/Output Function

University Of Texas Health Science Center San Antonio, San Antonio TX

Investigators

Abstract

Brain function is dependent upon proteins that allow ions to pass across neuron cell membranes (called ion channels) to create currents that mediate the electrical activity of neurons. Protein channels that permit potassium ions to pass through neuron membranes are generally thought to quiet excessive neuron activity. However, there is a growing list of examples indicating that these "BK-type" potassium ion channels may also increase neuron excitability. The fact that BK channels are expressed throughout the nervous system suggests that understanding such paradoxical effects is important for understanding brain function in general. The investigators will record the activity of neurons in mice to learn the conditions that cause BK channels to quiet or excite neurons. The results will be used to make computational models that predict the anti-excitatory or pro-excitatory behaviors of BK channels. The project will train graduate students and a postdoctoral fellow to use state-of-art methods for studying brain function and anatomy and to make computational models, and will support the development of an integrated online virtual laboratory, "The Ion Channel laboratory," to teach users about ion channels and the electrical excitability of neurons. The mechanisms underlying how slow- and fast-gating BK channel types either depress or paradoxically enhance a neuron's likelihood for firing an action potential (AP) will be studied in dentate gyrus neurons of the hippocampus. Using wild type neurons that express slow-gating BK channels, and transgenic neurons (BK beta4 knockout) that express fast-gating channels, the investigators will directly measure the cause-and-effect relationship between BK-regulated AP shape, activation of spike-triggered bulk and local calcium, recruitment of interspike conductances, and AP frequency. These data will be used to generate a computational model of dentate gyrus neurons that predicts the context in which BK channels reduce or enhance neuronal excitability. The model will then be experimentally tested in hippocampus CA1 pyramidal cells and cerebellum purkinje neurons to determine if pro-excitatory effects uncovered in dentate gyrus neurons are features observed in other neuron types that express BK channels. The findings of this study will create new understanding and new neuronal computational models of spike-influenced conductance and its effect on intrinsic excitability.