Synaptopodin regulates denervation-induced homeostatic synaptic plasticity

Abstract

Synaptopodin (SP) is a marker and essential component of the spine apparatus (SA), an enigmatic cellular organelle composed of stacked smooth endoplasmic reticulum that has been linked to synaptic plasticity. However, SP/SA-mediated synaptic plasticity remains incompletely understood. To study the role of SP/SA in homeostatic synaptic plasticity we here used denervation-induced synaptic scaling of mouse dentate granule cells as a model system. This form of plasticity is of considerable interest in the context of neurological diseases that are associated with the loss of neurons and subsequent denervation of connected brain regions. In entorhino-hippocampal slice cultures prepared from SP-deficient mice, which lack the SA, a compensatory increase in excitatory synaptic strength was not observed following partial deafferentation. In line with this finding, prolonged blockade of sodium channels with tetrodotoxin induced homeostatic synaptic scaling in wild-type, but not SP-deficient, slice cultures. By crossing SP-deficient mice with a newly generated transgenic mouse strain that expresses GFP-tagged SP under the control of the Thy1.2 promoter, the ability of dentate granule cells to form the SA and to homeostatically strengthen excitatory synapses was rescued. Interestingly, homeostatic synaptic strengthening was accompanied by a compensatory increase in SP cluster size/stability and SA stack number, suggesting that activity-dependent SP/SA remodeling could be part of a negative feedback mechanism that aims at adjusting the strength of excitatory synapses to persisting changes in network activity. Thus, our results disclose an important role for SP/SA in homeostatic synaptic plasticity.

Synaptic plasticity at the interface of health and disease: New insights on the role of endoplasmic reticulum intracellular calcium stores

“…While the precise cellular and molecular mechanisms through which SP/SA affect different forms of synaptic plasticity warrant additional investigation, experimental evidence has been provided for changes in SPexpression, SP-cluster sizes and stacking of SAs to accompany the induction of synaptic plasticity (Vlachos et al, 2009; see also Yamazaki et al, 2001;Fukazawa et al, 2003). These changes of SP/SA are activity-dependent, i.e., regulated by Ca 2+ entry through N-methyl-D-Aspartate receptors (NMDA-R) or L-type voltage-gated Ca 2+ channels (L-VGCC; Vlachos et al, 2013a) and seem to precede the induction of functional synaptic changes under certain experimental conditions Strehl et al, 2014). In line with work on the dynamics of spine ER, it was also demonstrated that the position of SP clusters can change in individual spines (Fig.…”

“…Synaptopodin (SP; Mundel et al, 1997;Asanuma et al, 2005) was recognized to be a marker (Deller et al, 2000) and essential component of the SA (Deller et al, 2003). SP-deficient mice lack SAs (and COs; Bas and show deficits in synaptic plasticity (Deller et al, 2003;Jedlicka et al, 2009;Zhang et al, 2013;Vlachos et al, 2013a;Korkotian et al, 2014). Meanwhile, experimental evidence has been provided that SP/SA Ca 2+ stores regulate different forms of synaptic plasticity: (1) RyR-dependent long-term potentiation (LTP) of synaptic strength was reported (Vlachos et al, 2009), as well as (2) mGluR-triggered IP3R-mediated synaptic depression, i.e., long-term depression (LTD) of excitatory synaptic strength (Holbro et al, 2009).…”

Estradiol responsiveness of synaptopodin in hippocampal neurons is mediated by estrogen receptor β

“…Mushroom spines, in turn, are considered to be "memory" spines, since they are functionally stronger, compared to thin spines, and can persist for months [17][18][19][20][21]. Synaptopodin is furthermore an actin-binding protein, thus it is likely that it plays a role in shaping spines via control of the spine cytoskeleton [22][23][24][25][26][27].…”

Roles of BMP6/7 in Actin Dynamics in Amyloid β-Induced Neurotoxicity

“…Second, late phase of LTP is dependent on protein synthesis to form new synapses (Fukazawa et al, 2003;Lisman et al, 2003). The actin pool is localized in specialized smooth endoplasmic reticulum, which is a spine apparatus to generate more actins, resulting in protrusion of new dendritic filopodia and spine outgrowth (Vlachos et al, 2013).…”