Deformation of Network Connectivity in the Inferior Olive of Connexin 36-Deficient Mice Is Compensated by Morphological and Electrophysiological Changes at the Single Neuron Level

Abstract

Compensatory mechanisms after genetic manipulations have been documented extensively for the nervous system. In many cases, these mechanisms involve genetic regulation at the transcription or expression level of existing isoforms. We report a novel mechanism by which single neurons compensate for changes in network connectivity by retuning their intrinsic electrical properties. We demonstrate this mechanism in the inferior olive, in which widespread electrical coupling is mediated by abundant gap junctions formed by connexin 36 (Cx36). It has been shown in various mammals that this electrical coupling supports the generation of subthreshold oscillations, but recent work revealed that rhythmic activity is sustained in knock-outs of Cx36. Thus, these results raise the question of whether the olivary oscillations in Cx36 knock-outs simply reflect the status of wild-type neurons without gap junctions or the outcome of compensatory mechanisms. Here, we demonstrate that the absence of Cx36 results in thicker dendrites with gap-junction-like structures with an abnormally wide interneuronal gap that prevents electrotonic coupling. The mutant olivary neurons show unusual voltage-dependent oscillations and an increased excitability that is attributable to a combined decrease in leak conductance and an increase in voltagedependent calcium conductance. Using dynamic-clamp techniques, we demonstrated that these changes are sufficient to transform a wild-type neuron into a knock-out-like neuron. We conclude that the absence of Cx36 in the inferior olive is not compensated by the formation of other gap-junction channels but instead by changes in the cytological and electroresponsive properties of its neurons, such that the capability to produce rhythmic activity is maintained.

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

“…2A). As previously reported for guinea pig (14), rat (17,26), mouse (27,28), and ferret (18), primate IO neurons demonstrated oscillations in membrane potential that were subthreshold for spiking (subthreshold oscillations, STOs) (Fig. 2 B-D and Fig.…”

“…2D). As demonstrated in rodents, the voltage insensitivity of STOs in IO neurons is supported by electronic coupling (14,27,28), and so the properties of primate IO neurons were consistent with their being coupled oscillators. Neither the properties nor the incidence of STOs differed among the experimental groups, although there was a trend toward slower STOs (3.1 ± 1.9 Hz) in CI neurons (Fig.…”

Estimating functional connectivity in an electrically coupled interneuron network

“…3B, b). The somatodendritic compartment had a somewhat larger capacitance in Cx36 −/− than in wild-type mice (6.2 ± 0.7 pF vs. 3.5 ± 0.4 pF, P = 0.02, Wilcoxon-Mann-Whitney two-sample test), which may reflect compensatory mechanisms in dendritic morphology as shown in other preparations (30), whereas the capacitance of the axonal compartment did not show any difference between wildtype and Cx36 −/− mice (P = 0.58, Wilcoxon-Mann-Whitney twosample test). The other parameters obtained in Cx36 −/− mice were A 1 = 790 ± 73 pA, τ 1 = 0.41 ± 0.05 ms and A 2 = 112 ± 15 pA, τ 2 = 3.7 ± 0.4 ms. P values for the comparison of the somatodendritic and axonal time constants τ 1 and τ 2 were, respectively, 0.26 and 0.51 (Wilcoxon-Mann-Withney two-sample rank test), confirming that these components do not reflect loading of coupled cells (Fig.…”

Normal motor learning during pharmacological prevention of Purkinje cell long-term depression

“…It is now well recognized that embryonic gene deletion or mutation can lead to unintended increases in the expression of untargeted proteins that may be compensatory to mask a phenotype (20,21,22) or secondary changes that may produce phenotypes not directly related to the targeted or mutant protein (23,24,25). Acute administration and rapid clearance of T-588 in the normal brain allows LTD to be transiently prevented without the consequences of an embryonic mutation.…”