Maintenance of Lognormal-Like Skewed Dendritic Spine Size Distributions in Dentate Granule Cells of TNF, TNF-R1, TNF-R2, and TNF-R1/2-Deficient Mice

Dendritic spines are sites of synaptic plasticity and their head size correlates with the strength of the corresponding synapse. We recently showed that the distribution of spine head sizes follows a lognormal-like distribution even after blockage of activity or plasticity induction. As the cytokine tumor necrosis factor (TNF) influences synaptic transmission and constitutive TNF and receptor (TNF-R)-deficiencies cause changes in spine head size distributions, we tested whether these genetic alterations disrupt the lognormality of spine head sizes. Furthermore, we distinguished between spines containing the actin-modulating protein synaptopodin (SP-positive), which is present in large, strong and stable spines and those lacking it (SP-negative). Our analysis revealed that neither TNF-deficiency nor the absence of TNF-R1, TNF-R2 or TNF-R 1 and 2 (TNF-R1/R2) degrades the general lognormal-like, skewed distribution of spine head sizes (all spines, SP-positive spines, SP-negative spines). However, TNF, TNF-R1 and TNF-R2-deficiency affected the width of the lognormal distribution, and TNF-R1/2-deficiency shifted the distribution to the left. Our findings demonstrate the robustness of the lognormal-like, skewed distribution, which is maintained even in the face of genetic manipulations that alter the distribution of spine head sizes. Our observations are in line with homeostatic adaptation mechanisms of neurons regulating the distribution of spines and their head sizes. Lognormal-like skewed spine size distribution is maintained in tumor necrosis factor deficiency and receptor loss. Dendritic spines sizes are distributed lognormally with a high percentage of the population consisting of small spines and a small percentage of the population consisting of large spines. The logarithm of the data shows a normal distribution. In mice exhibiting TNF deficiency, the lognormal distribution is maintained, albeit with a differences in its width, with the TNF deficient mice having more small and large sized spines and less medium sized spines. This finding was also observed in mice lacking TNF-receptor 1 and partially in mice lacking TNF-receptor 2. In mice lacking both TNF-receptor 1 and receptor 2 the lognormal distribution of spine head sizes was maintained, however, the distribution was shifted to the left, indicating a globalised reduction in spine head sizes of all spines. Spines maintain a lognormal distribution in multiple different conditions including homo- and heterosynaptic plasticity, blockage of presynaptic transmitter release and genetic disruption of TNF or its receptors, strenghtening the concept of redistribution of spine head sizes as a crucial functional adaptation within the neuron. image