Ampa Receptor Subunit Expression in the Endoplasmic Reticulum in Frontal Cortex of Elderly Patients with Schizophrenia

John C Hammond,Robert E Mccullumsmith,Vahram Haroutunian,James H Meador-Woodruff,Thomas Burne

doi:10.1371/journal.pone.0039190

John C Hammond, Robert E Mccullumsmith + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0039190

Copy DOI

Abstract

Several lines of evidence indicate altered trafficking of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors in schizophrenia. Previous reports have shown potential changes in the trafficking of AMPA receptors based on subunit expression of endosomes, subcellular organelles located near post-synaptic sites. We hypothesized that alterations in AMPA receptor trafficking through the endoplasmic reticulum (ER) may also be altered in schizophrenia. Accordingly, we developed a technique to isolate and measure content of the ER from postmortem brain tissue. We used Western blot and electron microscopy to show that we isolated an ER enriched fraction. We found no changes in the expression of the AMPA receptor subunits, GluR1–4, in the ER from the dorsolateral prefrontal cortex in schizophrenia. These data suggest that AMPA receptor trafficking through the ER is largely intact in schizophrenia.

Highlights

Schizophrenia, a severe mental illness, may be linked to abnormalities of glutamate receptor neurotransmission and expression [1,2,3]
We have previously reported increased expression in DLPFC in schizophrenia of Synapse-associated protein 97 (SAP97) and Glutamate Receptor Interacting Protein 1 (GRIP1), two proteins involved in the forward trafficking of AMPA receptors from the endoplasmic reticulum (ER) to the synapse [5]
We measured the expression of the AMPA receptor subunits, Glutamate Receptor 1 (GluR1)–4, in an ER enriched fraction from human brain

Summary

Introduction

Schizophrenia, a severe mental illness, may be linked to abnormalities of glutamate receptor neurotransmission and expression [1,2,3]. Recent evidence implicates abnormalities in trafficking of AMPA-type glutamate receptors in this illness [5,6,7]. AMPA receptor interacting proteins alter the rate of trafficking of AMPA receptors through the ER and to the synapse. Protein interacting with C Kinase 1 (PICK1) binds to the C-terminal domain of GluR2 in GluR2/GluR3 containing receptors, leading to slower exit from the ER [10]. Trafficking of assembled AMPA receptors from the ER to the distal dendrites occurs along the cytoskeletal spine. AMPA receptors in the distal dendrites can be surface expressed at the synapse in an activity-dependent manner [16,17]. Surface expressed AMPA receptors can be removed from and returned to the synapse in a tightly regulated endosomal system, facilitating changes in synaptic strength [18]

Methods

Results

Conclusion