Homeostatic Control of Synaptic Transmission by Distinct Glutamate Receptors

Yan, Dan; Yamasaki, Miwako; Straub, Christoph; Watanabe, Masahiko; Tomita, Susumu

doi:10.1016/j.neuron.2013.02.031

Cited by 31 publications

(37 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because global stg/γ-7 dKO mice did not exhibit such enhancement, rather a decrease relative to WT (Fig. 1 C and D), it is possible that this enhancement reflects a homeostatic effect of the late-onset loss of cf-EPSC responses as a way of maintaining synaptic activity, previously reported in stg CGNs (26). However, γ-2 PC KO; γ-7 WT mice showed no reduction in KA responses, indicating that approximately half of control levels of excitatory cf input onto PCs is sufficient to maintain essentially normal cerebellar function.…”

Section: Discussionmentioning

confidence: 68%

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Yamazaki

Pichon²,

Jackson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Transmembrane AMPA receptor regulatory proteins (TARPs) play an essential role in excitatory synaptic transmission throughout the central nervous system (CNS) and exhibit subtype-specific effects on AMPA receptor (AMPAR) trafficking, gating, and pharmacology. The function of TARPs has largely been determined through work on canonical type I TARPs such as stargazin (TARP γ-2), absent in the ataxic stargazer mouse. Little is known about the function of atypical type II TARPs, such as TARP γ-7, which exhibits variable effects on AMPAR function. Because γ-2 and γ-7 are both strongly expressed in multiple cell types in the cerebellum, we examined the relative contribution of γ-2 and γ-7 to both synaptic transmission in the cerebellum and motor behavior by using both the stargazer mouse and a γ-7 knockout (KO) mouse. We found that the loss of γ-7 alone had little effect on climbing fiber (cf) responses in Purkinje neurons (PCs), yet the additional loss of γ-2 all but abolished cf responses. In contrast, γ-7 failed to make a significant contribution to excitatory transmission in stellate cells and granule cells. In addition, we generated a PC-specific deletion of γ-2, with and without γ-7 KO background, to examine the relative contribution of γ-2 and γ-7 to PC-dependent motor behavior. Selective deletion of γ-2 in PCs had little effect on motor behavior, yet the additional loss of γ-7 resulted in a severe disruption in motor behavior. Thus, γ-7 is capable of supporting a component of excitatory transmission in PCs, sufficient to maintain essentially normal motor behavior, in the absence of γ-2.cerebellum | AMPA receptors | TARPs | stargazer | motor behavior N euronal excitability is controlled by two broad classes of ion channels: voltage-gated and ligand-gated. It is well established that voltage-gated channels are not only composed of pore-forming subunits but auxiliary subunits as well, which are not part of the pore, but control many important aspects of channel function, such as trafficking and gating (1, 2). In contrast, ligand-gated ion channels were thought to function independently of auxiliary subunits. The discovery of the tetraspanning membrane protein stargazin, also referred to as γ-2, which is mutated in the ataxic stargazer (stg) mouse, changed this view. Cerebellar granule neurons (CGNs), which express high levels of stargazin, were found to lack surface AMPA-type glutamate receptors (AMPARs) in the stg mouse (3, 4). Stargazin not only controls the trafficking of AMPARs, but also controls AMPAR gating (5-10), indicating that it satisfies all of the criteria of auxiliary subunits. Stargazin is a member of a family of proteins referred to as transmembrane AMPAR regulatory proteins (TARPs) and consists of the following members: canonical type I TARPs (γ-2, γ-3, γ-4, and γ-8) and atypical type II TARPs (γ-5 and γ-7), which differ in their amino acid sequence and uniquely regulate AMPAR trafficking, gating, and neuropharmacology (7).Of particular interest is TARP γ-7, which is expressed throughout the brain...

show abstract

Section: Discussionmentioning

confidence: 68%

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Yamazaki

Pichon²,

Jackson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In cerebellar granule cells, the native KAR complex consists of GluK2, GluK5, and Neto2 (Yan et al, 2013). GluK2 and Neto2 are detected in the PSD fraction of both wild-type and GluK5 KO mice at similar levels (Yan et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…This restricted localization of KARs is apparent in the hippocampal stratum lucidum where mossy fiber axons projecting from dentate gyrus granule neurons form complex synapses with CA3 neurons (Castillo et al, 1997; Contractor et al, 2003; Darstein et al, 2003; Mulle et al, 1998; Petralia et al, 1994; Vignes and Collingridge, 1997). In contrast, KARs are found at all synapses in the cerebellum, where granule cells receive input from only one type of excitatory afferent, the mossy fiber (Yan et al, 2013). Mechanisms underlying these synaptic differences remain unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Because KAR-mediated transmission is absent in primary cultured hippocampal neurons (Lerma et al, 1993), studying synapses in vivo using mouse gene-targeting approaches has been particularly useful in identifying KAR components required for synaptic localization and function. Knockout of the primary low-affinity subunit GluK2 abolishes KAR currents as well as localization of receptors (Mulle et al, 1998; Yan et al, 2013). In addition, GluK2 KO mice exhibit reduced expression of other components of the native KAR complexes, GluK4/5 and Neto1/2 (Christensen et al, 2004; Nasu-Nishimura et al, 2006; Ruiz et al, 2005; Straub et al, 2011; Zhang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Distinct Subunit Domains Govern Synaptic Stability and Specificity of the Kainate Receptor

et al. 2016

Self Cite

View full text Add to dashboard Cite

Synaptic communication between neurons requires the precise localization of neurotransmitter receptors to the correct synapse type. Kainate-type glutamate receptors have restricted synaptic localization that is determined by the afferent presynaptic connection. The mechanisms that govern this input-specific synaptic localization remain unclear. Here we examine how subunit composition and specific subunit domains contribute to synaptic localization of kainate receptors. The cytoplasmic domain of the GluK2 low-affinity subunit stabilized kainate receptors at synapses. In contrast, the extracellular domain of the GluK4/5 high-affinity subunit synergistically controls the synaptic specificity of kainate receptors through interaction with C1q-like proteins. Thus the input-specific synaptic localization of the native kainate receptor complex involves two mechanisms that underlie specificity and stabilization of the receptor at synapses.

show abstract

“…The efficiency of the knockout of the GluK5 gene has not been tested sufficiently by the developers. In fact, a recent study using GluK5 KO mice found no difference between KO and WT in electrophysiological findings and expression level of synaptic proteins (Yan et al, 2013). …”

Section: Resultsmentioning

confidence: 99%

Localization of kainate receptors in inner and outer hair cell synapses

et al. 2014

View full text Add to dashboard Cite

Glutamate plays a role in hair cell afferent transmission, but the receptors that mediate neurotransmission between outer hair cells (OHCs) and type II ganglion neurons are not well defined. A previous study using in situ hybridization showed that several kainate-type glutamate receptor (KAR) subunits are expressed in cochlear ganglion neurons. To determine whether KARs are expressed in hair cell synapses, we performed X-gal staining on mice expressing lacZ driven by the GluK5 promoter, and immunolabeling of glutamate receptors in whole-mount mammalian cochleae. X-gal staining revealed GluK5 expression in both type I and type II ganglion neurons and OHCs in adults. OHCs showed X-gal reactivity throughout maturation from postnatal day 4 (P4) to 1.5 months. Immunoreactivity for GluK5 in IHC afferent synapses appeared to be postsynaptic, similar to GluA2 (GluR2; AMPA-type glutamate receptor (AMPAR) subunit), while GluK2 may be on both sides of the synapses. In OHC afferent synapses, immunoreactivity for GluK2 and GluK5 was found, although GluK2 was only in those synapses bearing ribbons. GluA2 was not detected in adult OHC afferent synapses. Interestingly, GluK1, GluK2 and GluK5 were also detected in OHC efferent synapses, forming several active zones in each synaptic area. At P8, GluA2 and all KAR subunits except GluK4 were detected in OHC afferent synapses in the apical turn, and GluA2, GluK1, GluK3 decreased dramatically in the basal turn. These results indicate that AMPARs and KARs (GluK2/GluK5) are localized to IHC afferent synapses, while only KARs (GluK2/GluK5) are localized to OHC afferent synapses in adults. Glutamate spillover near OHCs may act on KARs in OHC efferent terminals to modulate transmission of acoustic information and OHC electromotility.

show abstract

Homeostatic Control of Synaptic Transmission by Distinct Glutamate Receptors

Cited by 31 publications

References 69 publications

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Distinct Subunit Domains Govern Synaptic Stability and Specificity of the Kainate Receptor

Localization of kainate receptors in inner and outer hair cell synapses

Contact Info

Product

Resources

About