Temperature Deactivation of the Depolarizing TRP Current as a Mechanism of Hypothermia-Related Inhibition of Neuronal Activity: a Model Study

Therapeutic neuroprotective hypothermia is becoming increasingly used to suppress abnormally high neuronal activity in the brain occurring under conditions of ischemic and traumatic injuries, refractory epilepsy, etc. This makes especially topical examination of the factors determining the temperature dependence of the intensity of neuronal excitation. In this respect, of interest are thermosensitive TRP-type channels conducting depolarization currents and found in central neurons. We explored such channels and their functional role using computer modeling. These channels were present in the membrane of a simulated dentate gyrus granule cell of the hippocampus. The chanels can be in two states, open and closed, and the probabilities of these states are temperature-dependent. The model adequately reproduced the key feature of the prototype, namely voltage-dependent activation of TRP channels shifted toward depolarization with a decrease in the temperature. At identical potentials, the level of such activation was reduced, i.e., a deactivation phenomenon was observed. The decrease of temperature from 37°C (normothermia) to 20°C (focal deep hypothermia) was accompanied by a significant decrease in the frequency of action potentials generated by the simulated neuron in response to tonic synaptic excitation of the same intensity. This hypothermic inhibition was most pronounced within the temperature range where temperature-dependent deactivation of TRP channels developed. This effect was much less manifested in the case where TRP channels were “turned off,” which mimicked their genetic knockout. Such results obtained on a rather simplified model reveal new aspects of the neuroprotective effect of hypothermia, which deserves further in-depth studies.