The function of glutamatergic synapses is not perturbed by severe knockdown of 4.1N and 4.1G expression

Abstract

AMPA-type glutamate receptors mediate fast excitatory synaptic transmission in the vertebrate brain. Their surface expression at synapses between neurons is regulated in an activity-dependent and activity-independent manner. The protein machinery that regulates synaptic targeting, anchoring and turnover of AMPA receptors consists of several types of specialized scaffolding proteins. The FERM domain scaffolding proteins 4.1G and 4.1N were previously suggested to act jointly in binding and regulating synaptic trafficking of the AMPA receptor subunits GluR1 and GluR4. To determine the functions of 4.1G and 4.1N in vivo, we generated a mutant mouse line that lacks 4.1G entirely and expresses 4.1N at 22% of wild-type levels. These mice had combined 4.1G and 4.1N protein expression in the hippocampus at 12% of wild-type levels (equivalent to 8-10% of combined GluR1 and GluR4 expression levels). They show a moderate reduction in synaptosomal expression levels of the AMPA receptor subunit GluR1 at 3 weeks of age, but no change in basic glutamatergic synaptic transmission and long-term potentiation in the hippocampus. Our study indicates that 4.1G and 4.1N do not have a crucial role in glutamatergic synaptic transmission and the induction and maintenance of long-term plastic changes in synaptic efficacy.

Protein-4.1G-Mediated Membrane Trafficking Is Essential for Correct Rod Synaptic Location in the Retina and for Normal Visual Function

“…The immunostained 4.1G signal totally disappeared in the 4.1G À/À retina ( Figure S1P), indicating that the 4.1G À/À mice are 4.1G-null mutants. Both 4.1G +/À and 4.1G À/À mice were viable and showed no gross morphological abnormalities, whereas 4.1G À/À male mice are infertile as reported previously (Wozny et al, 2009). We next immunostained PSD95 and pikachurin in retinal sections at 2 months old (2M) to label photoreceptor synaptic terminals.…”

Kainate Receptor Post-translational Modifications Differentially Regulate Association with 4.1N to Control Activity-dependent Receptor Endocytosis

“…Proximal phosphorylation of the GluA1 C terminus promotes 4.1N association, which is antagonized by palmitoylation within this domain (9). How these modulatory systems impact synaptic signaling is less clear because gene-targeted mice lacking 4.1G and with reduced 4.1N expression exhibit no apparent deficits in NMDA receptor-dependent long term potentiation (37). AMPA and kainate receptors perform different functions in the CNS; in part, this arises from very distinct gating kinetics of postsynaptic receptors, which have important consequences on neuronal excitability, particularly during repetitive activation (38).…”

Organization of Myelinated Axons by Caspr and Caspr2 Requires the Cytoskeletal Adapter Protein 4.1B

“…Interestingly, an increase in the expression of 4.1G in the heart, as well as 4.1N in T cells, was reported in mice lacking 4.1R (Stagg et al, 2008). Redundancy between 4.1 proteins was also suggested to explain the difference between in vitro (Lin et al, 2009) and in vivo (Wozny et al, 2009) role of 4.1N and 4.1G in the formation of glutamatergic synapses. Given that protein 4.1R accumulates at the PNJ in mice lacking 4.1B, it will require the generation of double 4.1B/4.1R null mice to further understand the role of these proteins in myelinated axons.…”