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Introduction: Neuronal death and subsequent denervation of target areas are hallmarks of many neurological disorders. Denervated neurons lose part of their dendritic tree, and are considered "atrophic", i.e. pathologically altered and damaged. The functional consequences of this phenomenon are poorly understood.
Results: Using computational modelling of 3D-reconstructed granule cells we show that denervation-induced dendritic atrophy also subserves homeostatic functions: By shortening their dendritic tree, granule cells compensate for the loss of inputs by a precise adjustment of excitability. As a consequence, surviving afferents are able to activate the cells, thereby allowing information to flow again through the denervated area. In addition, action potentials backpropagating from the soma to the synapses are enhanced specifically in reorganized portions of the dendritic arbor, resulting in their increased synaptic plasticity. These two observations generalize to any given dendritic tree undergoing structural changes.
Conclusions: Structural homeostatic plasticity, i.e. homeostatic dendritic remodeling, is operating in long-term denervated neurons to achieve functional homeostasis.
Poster presentation: Twenty Second Annual Computational Neuroscience Meeting: CNS*2013. Paris, France. 13-18 July 2013.
Neuronal death and subsequent denervation of target areas is a major feature of several neurological conditions such as brain trauma, ischemia or neurodegeneration. The denervation-induced axonal loss results in reorganization of the dendritic tree of denervated neurons. Dendritic reorganization of denervated neurons has been previously studied using entorhinal cortex lesion (ECL).
ECL leads to shortening and loss of dendritic segments in the denervated outer molecular layer of the dentate gyrus [1]. However, the functional importance of these long-term dendritic alterations is not yet understood and their impact on neuronal electrical properties remains unclear. Therefore, in this study we analyzed what happens to the electrotonic structure and excitability of dentate granule cells after denervation-induced alterations of their dendritic morphology, assuming all other parameters remain equal.
To perform comparative electrotonic analysis we used computer simulations in anatomically and biophysically realistic compartmental models of 3D-reconstructed healthy and denervated granule cells. Our results show that somatofugal and somatopetal voltage attenuation due to passive cable properties was strongly reduced in denervated granule cells. In line with these predictions, the attenuation of simulated backpropagating action potentials and forward propagating EPSPs was significantly reduced in dendrites of denervated neurons. In addition, simulations of somatic and dendritic frequency-current (f-I) curves revealed increased excitability in deafferentated granule cells.
Taken together, our results indicate that unless counterbalanced by a compensatory adjustment of passive and/or active membrane properties, the plastic remodeling of dendrites following lesion of entorhinal cortex inputs to granule cells will boost their electrotonic compactness and excitability.
Large spines are stable and important for memory trace formation. The majority of large spines also contains synaptopodin (SP), an actin-modulating and plasticity-related protein. Since SP stabilizes F-actin, we speculated that the presence of SP within large spines could explain their long lifetime. Indeed, using 2-photon time-lapse imaging of SP-transgenic granule cells in mouse organotypic tissue cultures we found that spines containing SP survived considerably longer than spines of equal size without SP. Of note, SP-positive (SP+) spines that underwent pruning first lost SP before disappearing. Whereas the survival time courses of SP+ spines followed conditional two-stage decay functions, SP-negative (SP-) spines and all spines of SP-deficient animals showed single-phase exponential decays. This was also the case following afferent denervation. These results implicate SP as a major regulator of long-term spine stability: SP clusters stabilize spines, and the presence of SP indicates spines of high stability.
The majority of excitatory synapses terminating on cortical neurons are found on dendritic spines. The geometry of spines, in particular the size of the spine head, tightly correlates with the strength of the excitatory synapse formed with the spine. Under conditions of synaptic plasticity, spine geometry may change, reflecting functional adaptations. Since the cytokine tumor necrosis factor (TNF) has been shown to influence synaptic transmission as well as Hebbian and homeostatic forms of synaptic plasticity, we speculated that TNF-deficiency may cause concomitant structural changes at the level of dendritic spines. To address this question, we analyzed spine density and spine head area of Alexa568-filled granule cells in the dentate gyrus of adult C57BL/6J and TNF-deficient (TNF-KO) mice. Tissue sections were double-stained for the actin-modulating and plasticity-related protein synaptopodin (SP), a molecular marker for strong and stable spines. Dendritic segments of TNF-deficient granule cells exhibited ∼20% fewer spines in the outer molecular layer of the dentate gyrus compared to controls, indicating a reduced afferent innervation. Of note, these segments also had larger spines containing larger SP-clusters. This pattern of changes is strikingly similar to the one seen after denervation-associated spine loss following experimental entorhinal denervation of granule cells: Denervated granule cells increase the SP-content and strength of their remaining spines to homeostatically compensate for those that were lost. Our data suggest a similar compensatory mechanism in TNF-deficient granule cells in response to a reduction in their afferent innervation.
The majority of excitatory synapses terminating on cortical neurons are found on dendritic spines. The geometry of spines, in particular the size of the spine head, tightly correlates with the strength of the excitatory synapse formed with the spine. Under conditions of synaptic plasticity, spine geometry may change, reflecting functional adaptations. Since the cytokine tumor necrosis factor (TNF) has been shown to influence synaptic transmission as well as Hebbian and homeostatic forms of synaptic plasticity, we speculated that TNF-deficiency may cause concomitant structural changes at the level of dendritic spines. To address this question, we analyzed spine density and spine head area of Alexa568-filled granule cells in the dentate gyrus of adult C57BL/6J and TNF-deficient (TNF-KO) mice. Tissue sections were double-stained for the actin-modulating and plasticity-related protein synaptopodin (SP), a molecular marker for strong and stable spines. Dendritic segments of TNF-deficient granule cells exhibited ∼20% fewer spines in the outer molecular layer of the dentate gyrus compared to controls, indicating a reduced afferent innervation. Of note, these segments also had larger spines containing larger SP-clusters. This pattern of changes is strikingly similar to the one seen after denervation-associated spine loss following experimental entorhinal denervation of granule cells: Denervated granule cells increase the SP-content and strength of their remaining spines to homeostatically compensate for those that were lost. Our data suggest a similar compensatory mechanism in TNF-deficient granule cells in response to a reduction in their afferent innervation.
