Sushi domain-containing protein 4 controls synaptic plasticity and motor learning

Abstract

Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here we show that Susd4, a gene coding for a complement-related transmembrane protein, is expressed by many neuronal populations starting at the time of synapse formation. Constitutive loss-of-function of Susd4 in the mouse impairs motor coordination adaptation and learning, prevents long-term depression at cerebellar synapses, and leads to misregulation of activity-dependent AMPA receptor subunit GluA2 degradation. We identified several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, as SUSD4 binding partners. Our findings shed light on the potential role of SUSD4 mutations in neurodevelopmental diseases.

Designing AAV Vectors for Monitoring the Subtle Calcium Fluctuations of Inferior Olive Network in vivo

“…Most of the constructs, including Igsf9, Pdx1 and Susd4 (that have previously been shown to drive IO-specific transgene expression when used in cre-transgenic animals) drove stronger overall expression in the regions surrounding the IO ( Figure 1C , datapoints to the right of the vertical dashed line). Notably, GFP-expressing IO cells were seen densely labeled in limited region of the dorsomedial IO (2 out of 4 mice, subnucleus IO-Be, see arrow in Figure 1A2 ) with the Susd4-promoter (González-Calvo et al, 2021 ), but the expression was seen only sparsely within the other IO subnuclei.…”

“…The longest version of the Htr5b-promoter that we previously judged as having the strongest tropism for IO over the surrounding structures ( Figure 1 ) also resulted in the cleanest neuron-specificity (neuron/astrocyte ratio for Htr5b(3.7) promoter: +40 ± 9.8%, n = 79 cells; for all values, see Table 1 ). Notably, even though Susd4, Pdx1 and Igsf9-promoters have been shown to preferentially label IO neurons when used in the form of a transgenic animal (Hansen and Walmod, 2013 ; González-Calvo et al, 2021 ), this was not observed using AAV9-based transfection. Susd4 and Pdx1-controlled expression was only weakly biased toward neurons, and the neuronal expression obtained with various clones of Igsf9 promoter were same or less than that in astrocytes in the same slices.…”

“…Susd4 (Sushi Domain Containing 4; González-Calvo et al, 2021 ) gene promoter is driving expression of adhesion molecules in the axons of IO neurons.…”

“…Despite several works having employed a generic targeting approach for IO (White and Sillitoe, 2017 ; Rowan et al, 2018 ; Gaffield et al, 2019 ; González-Calvo et al, 2021 ), no systematic effort has been made to create a more specific targeting tool. Instead, experimenters have resorted to indirect methods, such as imaging IO-axon-evoked spikes in the cerebellum (Ju et al, 2019 ; Hoang et al, 2020 ; Roh et al, 2020 ; Michikawa et al, 2021 ), optogenetic modulation of IO afferents instead of IO neurons (Kim et al, 2020 ), limiting experimentation to cerebellar cortical regions where off-target transfection of axons with, e.g., the CamKII promoter is not problematic (Mathews et al, 2012 ; Gaffield et al, 2019 ) or morphological analysis (Nishiyama et al, 2007 ; Pätz et al, 2018 ; Vrieler et al, 2019 ; González-Calvo et al, 2021 ). To our knowledge, there have been no published reports of in situ, in vivo multi-cell IO network activity besides our recently-published preliminary observations (Guo et al, 2021 ).…”

Synapse Formation and Function Across Species: Ancient Roles for CCP, CUB, and TSP-1 Structural Domains

“…( Boulanger, 2009 )). One particular category of immune-related proteins with neuronal function are the proteins of the complement system implicated in innate immunity or their regulators: the complement proteins C1q and C3 contribute to synaptic pruning in the developing brain ( Stephan et al, 2012 ) and the complement inhibitor SUSD4 (Sushi domain-containing protein 4) regulates synaptic plasticity ( González-Calvo et al, 2021 ). Invertebrates do not have a complement system or an adaptative immune system.…”