| Abstract No.: | 209 |
| Country: | USA |
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| Title: | Failure of Inhibition Through Collapse of the Cloride Gradient |
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| Authors/Affiliations: | Steven A. Prescott,
Salk Institute, Computational Neurobiology, La Jolla, CA, USA |
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| Content: | Reduction of synaptic inhibition has been implicated in the pathogenesis of neurological disorders such as epilepsy and neuropathic pain. One mechanism through which GABAA/glycine receptor-mediated inhibition can be compromised is by reduction of the transmembrane chloride gradient via changes in chloride pumps. The resulting shift in chloride reversal potential reduces hyperpolarization mediated by GABAA/glycine receptors, but those receptors are thought to act predominantly by shunting excitatory input; shunting should remain intact regardless of chloride reversal potential. What, then, is the biophysical basis for the obvious behavioural consequences of disinhibition caused by collapse of the chloride gradient? Using computer simulations, we have shown that shunting-mediated modulation of firing rate depends on the balance between two opposing mechanisms: shunting reduces excitation-induced depolarization, but it also shortens the membrane time constant which translates into faster membrane charging and increased spiking. The latter mechanism predominates when average depolarization is suprathreshold. Disinhibition therefore occurs as both hyperpolarization- and shunting-mediated modulation of firing rate are subverted by reduction of chloride reversal potential. Small reductions may be compensated by increased GABAA/glycine receptor-mediated input, but the system decompensates (i.e. compensation fails) as reduction of chloride reversal exceeds a critical value. Hyperexcitability necessarily develops once disinhibition becomes incompensable. This knowledge has important therapeutic implications for how to correct disinhibition caused by changes in chloride homeostasis.
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