Paul Pfeiffer: Beyond standard models of neural excitability - when channels cooperate or capacitance varies

BCCN Berlin / GRK 1589 / Humboldt-Universität zu Berlin

Abstract

Electrical signaling in neurons is shaped by their specialized excitable cell membranes. Commonly, it is assumed that the ion channels embedded in the membrane gate independently and that the electrical capacitance of neurons is constant. However, not all excitable membranes appear to adhere to these assumptions. On the contrary, ion channels are observed to gate cooperatively in several circumstances and also the notion of one fixed value for the specific membrane capacitance (per unit area) across neuronal membranes has been challenged recently. How these deviations from the original form of conductance-based neuron models affect the electrical properties of nerve cells has not been extensively explored and is the focus of this cumulative thesis.

In the first project, strongly cooperative voltage-gated ion channels are proposed to provide a membrane potential-based mechanism for cellular short-term memory. Based on a mathematical model of cooperative gating, it is shown that coupled channels assembled into small clusters act as an ensemble of bistable conductances. The correspondingly large memory capacity of such an ensemble yields an alternative explanation for graded forms of cell-autonomous persistent firing – a firing mode observed in several brain regions that could serve to store transient information in the activity levels of single cells. Accordingly, this mnemonic firing mode could be evoked in biological neurons by “injection” of cooperative channels via the dynamic clamp. Cooperative gating might hence present a form of cellular positive feedback that complements other memory-serving feedback mechanisms on the network level.

In the second project, a novel dynamic clamp protocol -- the capacitance clamp -- is developed to artificially modify capacitance in biological neurons. Experimental means to systematically investigate capacitance, a basic parameter shared by all excitable cells, had previously been missing. The technique, thoroughly tested in simulations and experiments, is shown to alter the membrane time constant and the cell impedance as expected for a capacitance change. By monitoring how capacitance thereby affects temporal integration and energetic costs of spiking in dentate gyrus granule cells, it is demonstrated how the capacitance clamp will serve as a new tool to characterize a neuron's dynamical repertoire and to understand the adaptive function of exceptional capacitance values.

Summarizing, this thesis predicts a new role for cooperative gating as an efficient neuronal memory mechanism and provides a precise and robust method to study capacitance variations in real neurons. Combined, the projects identify computationally relevant consequences of these often neglected facets of neuronal membranes and extend the modeling and experimental techniques to further study them.

 

Additional Information

PhD defense in the research training group GRK 1589, 'Sensory Computation in Neural Systems'.

Organized by

Prof. Dr. Susanne Schreiber & Prof. Dr. Imre Vida