TARP γ-7 selectively enhances synaptic expression of calcium-permeable AMPARs

Studniarczyk, Dorota; Coombs, Ian D.; Cull-Candy, SG; Farrant, M

doi:10.1038/nn.3473

Cited by 45 publications

(52 citation statements)

References 58 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3). These results appear to differ substantially from previous results in which shRNA of γ-7 in stg CGNs resulted in a rescue of synaptic and whole-cell currents (17,18). What might account for the difference?…”

Section: Excitatory Transmission In Cultured Cerebellar Granule Cells Iscontrasting

confidence: 99%

“…To address this possibility, we used the same shRNA constructs to knock down γ-7 in cultured stg CGNs. In our hands, the fluorescence of the γ-7-shRNA-mCherry constructs reported (17,18) was quite weak in CGNs. However, in stg CGNs expressing the shRNA-mCherry constructs, we failed to see any rescue of sEPSCs in contrast with previous reports.…”

Section: Excitatory Transmission In Cultured Cerebellar Granule Cells Ismentioning

confidence: 67%

“…Remarkably both manipulations caused a large increase in AMPAR currents, but their subunit composition differed. With knockdown, the additional receptors contained GluA2, whereas with overexpression, the additional receptors lacked GluA2 (18). Overall, these results suggest an intriguing interplay between γ-7 and γ-2 among neuronal cell types in the cerebellar cortex that may exhibit cell-type specificity.…”

mentioning

confidence: 80%

“…TARP γ-7 is expressed ubiquitously in the cerebellum, from the abundant CGNs to cerebellar interneurons (such as SCs) and in the only output neurons of the cerebellum, the PCs (11,12,14). In addition, recent work suggests that γ-7 has specialized roles to play in compartment-and subunit-specific AMPAR trafficking in SCs and CGNs (17,18).…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

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: Excitatory Transmission In Cultured Cerebellar Granule Cells Iscontrasting

confidence: 99%

Section: Excitatory Transmission In Cultured Cerebellar Granule Cells Ismentioning

confidence: 67%

mentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

“…Consistent with the absence of γ2 these synaptic CP-AMPARs exhibited low conductance and were blocked by spermine 123 (but see 124 ). In cerebellar granule cells, another TARP, γ7, promotes surface expression of CP-AMPARs while restricting surface expression of CI-AMPARs 125 . Interestingly, however, neither γ7-associated CP-AMPARs nor CI-AMPARs are synaptically expressed unless the complex also contains γ2.…”

Section: Ampar Auxiliary Subunitsmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

View full text Add to dashboard Cite

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

show abstract

Zebrafish TARP Cacng2 is required for the expression and normal development of AMPA receptors at excitatory synapses

Roy

Ahmed

Cunningham

et al. 2015

Developmental Neurobiology

View full text Add to dashboard Cite

Fast excitatory synaptic transmission in the CNS is mediated by the neurotransmitter glutamate, binding to and activating AMPA receptors (AMPARs). AMPARs are known to interact with auxiliary proteins that modulate their behavior. One such family of proteins is the transmembrane AMPA receptor-related proteins, known as TARPs. Little is known about the role of TARPs during development, or about their function in non-mammalian organisms. Here we report the presence of TARPs, specifically the prototypical TARP, stargazin, in developing zebrafish. We find that zebrafish express two forms of stargazin, Cacng2a and Cacng2b from as early as 12-h post fertilization (hpf). Knockdown of Cacng2a and Cacng2b via splice-blocking morpholinos resulted in embryos that exhibited deficits in C-start escape responses, showing reduced C-bend angles, smaller tail velocities and aberrant C-bend turning directions. Injection of the morphants with Cacng2a or 2b mRNA rescued the morphological phenotype and the synaptic deficits. To investigate the effect of reduced Cacng2a and 2b levels on synaptic physiology, we performed whole cell patch clamp recordings of AMPA mEPSCs from zebrafish Mauthner cells. Knockdown of Cacng2a results in reduced AMPA currents and lower mEPSC frequencies, whereas knockdown of Cacng2b displayed no significant change in mEPSC amplitude or frequency. Non-stationary fluctuation analysis confirmed a reduction in the number of active synaptic receptors in the Cacng2a but not in the Cacng2b morphants. Together, these results suggest that Cacng2a is required for normal trafficking and function of synaptic AMPARs, while Cacng2b is largely non-functional with respect to the development of AMPA synaptic transmission.

show abstract

TARP γ-7 selectively enhances synaptic expression of calcium-permeable AMPARs

Cited by 45 publications

References 58 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

Synaptic AMPA receptor composition in development, plasticity and disease

Zebrafish TARP Cacng2 is required for the expression and normal development of AMPA receptors at excitatory synapses

Contact Info

Product

Resources

About