Slow excitatory synaptic currents generated by AMPA receptors

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein phosphatase that regulates a variety of synaptic proteins, including NMDA receptors (NAMDRs). To better understand STEP’s effect on other receptors, we used mass spectrometry to identify the STEP61 interactome. We identified a number of known interactors, but also ones including the GluA2 subunit of AMPA receptors (AMPARs). We show that STEP61 binds to the C termini of GluA2 and GluA3 as well as endogenous AMPARs in hippocampus. The synaptic expression of GluA2 and GluA3 is increased in STEP-KO mouse brain, and STEP knockdown in hippocampal slices increases AMPAR-mediated synaptic currents. Interestingly, STEP61 overexpression reduces the synaptic expression and synaptic currents of both AMPARs and NMDARs. Furthermore, STEP61 regulation of synaptic AMPARs is mediated by lysosomal degradation. Thus, we report a comprehensive list of STEP61 binding partners, including AMPARs, and reveal a central role for STEP61 in differentially organizing synaptic AMPARs and NMDARs.

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Two Families of TARP Isoforms that Have Distinct Effects on the Kinetic Properties of AMPA Receptors and Synaptic Currents

Neuron ◽

10.1016/j.neuron.2007.08.024 ◽

2007 ◽

Vol 55 (6) ◽

pp. 890-904 ◽

Cited By ~ 104

Author(s):

Chang-Hoon Cho ◽

Fannie St-Gelais ◽

Wei Zhang ◽

Susumu Tomita ◽

James R. Howe

Keyword(s):

Ampa Receptors ◽

Kinetic Properties ◽

Synaptic Currents

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Theta-Frequency Facilitation of AMPA Receptor-Mediated Synaptic Currents in the Principal Cells of the Medial Septum

Journal of Neurophysiology ◽

10.1152/jn.2001.85.4.1709 ◽

2001 ◽

Vol 85 (4) ◽

pp. 1709-1718 ◽

Cited By ~ 15

Author(s):

John N. Armstrong ◽

Brian A. MacVicar

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

Laser Scanning ◽

Medial Septum ◽

Laser Scanning Microscopy ◽

Projection Neurons ◽

Synaptic Currents ◽

External Application ◽

Septal Neurons ◽

Current Facilitation

Recent evidence suggests that Ca2+-permeable AMPA receptors display rapid, short-lasting current facilitation. In this study, we investigated the properties of AMPA receptor-mediated synaptic currents in medial septal neurons of the rat in an in vitro slice preparation. Immunocytochemistry with a selective antibody to the GluR2 subunit revealed that both choline acetyltransferase-containing and parvalbumin-containing neurons of the medial septum express no detectable GluR2 subunit immunoreactivity. We used whole cell voltage-clamp recordings to measure synaptically evoked AMPA receptor-mediated currents from medial septal neurons following stimulation of midline afferents. The GYKI 52466 (50 μM)- and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) (20 μM)-sensitive AMPA receptor-mediated component of the synaptic response was isolated by blocking GABAA- and N-methyl-d-aspartate receptor-mediated currents with 30 μM bicuculline and 100 μM 2-amino-5-phosphonovaleric acid, respectively. In some cases, patched cells were filled with Lucifer yellow (0.1%) and imaged using 2-photon laser scanning microscopy. AMPA receptor-mediated currents that were observed in large medial septal neurons (20–30 μm) displayed rectification. These currents were sensitive to external application of philanthotoxin-343 (PhTx-343, 50 μM), a potent, high-affinity antagonist of Ca2+-permeable, GluR2-lacking AMPA receptors. Rectifying AMPA receptor-mediated currents also displayed a rapid increase in amplitude when evoked five times at low frequency such as 6 Hz. In contrast to currents observed in large medial septal neurons, AMPA-receptor mediated currents evoked in the remaining small (8–11 μm) neurons were nonrectifying and displayed rapid synaptic depression when stimulated five times at 6 Hz. The currents evoked in these cells were unaffected by external application of PhTx-343 and were therefore GluR2-containing AMPA receptors. The results of the present study demonstrate that the principal projection neurons of the medial septum contain PhTx-343-sensitive, GluR2-lacking AMPA receptors that display rapid current facilitation when stimulated at low frequencies.

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