Abstract
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.
Highlights
Dendritic spines are highly motile protrusions on dendrites of many neurons in the central nervous system (Dunaevsky et al, 2001) forming axo-spinous synapses with glutamatergic afferents (DeFelipe et al, 1988)
Previous work showed that Tumor necrosis factor (TNF) is an important factor in the control of synaptic strength (Beattie et al, 2002; Santello et al, 2011; Stellwagen et al, 2005; Stück et al, 2012)
Since synaptic strength and spine geometry are tightly linked (Bonhoeffer & Yuste, 2002; Fifková & van Harreveld, 1977; Kasai et al, 2003; Matsuzaki et al, 2004), we speculated that genetic knockout of TNF in vivo may have a structural correlate at the level of spines
Summary
Dendritic spines are highly motile protrusions on dendrites of many neurons in the central nervous system (Dunaevsky et al, 2001) forming axo-spinous synapses with glutamatergic afferents (DeFelipe et al, 1988). Since TNF reduces GABAergic transmission by promoting GABAa-receptor endocytosis (Stellwagen et al, 2005), TNF has been suggested to play a role in the fine tuning of excitation/inhibition of neuronal networks (Santello & Volterra, 2012; Stellwagen et al, 2005) These physiological functions of TNF, which require only basal concentrations of the cytokine are considered largely distinct from TNF actions in pathophysiological contexts (Heir & Stellwagen, 2020; Santello & Volterra, 2012)
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