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GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal formation in schizophrenia:
S L Eastwood1, P W Burnet, P J Harrison
1University Department of Psychiatry, Warneford Hospital, Oxford, UK.
Abstract:
GluR2 is the key subunit of heteromeric AMPA-preferring glutamate receptors. GluR2 mRNA has been shown by in situ hybridization histochemistry to be decreased in the hippocampal formation in schizophrenics. Here, a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method was used to investigate GluR2 expression further and to examine the relative abundance of its alternatively spliced mRNA isoforms ('flip' and 'flop') in 11 schizophrenics and 11 matched controls. Compared to the controls, schizophrenics showed reduced expression of both isoforms relative to cyclophilin mRNA, but a greater loss of the flop isoform led to a higher flip:flop ratio. These differences were observed having controlled for the confounding effects of brain pH and age upon the mRNAs. We also found that the abundance of GluR2 mRNA correlates with that of the encoded subunit. This study has confirmed that, in schizophrenia, hippocampal GluR2 mRNA is reduced, and indicates that GluR2 subunits are composed of a higher proportion of the flip variant. These data extend the evidence for glutamatergic dysfunction in the disease. They suggest that signal transduction through hippocampal AMPA receptors is impaired in schizophrenia both by an overall loss of GluR2 expression, and by the change in flip:flop ratio which is predicted to alter the desensitization kinetics of the remaining GluR2 subunits.
Insights
Schizophrenia is linked to reduced GluR2 mRNA in the hippocampus, affecting AMPA receptors. This study found a higher flip:flop ratio, impacting receptor function and signaling in the brain.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Glutamate receptors, specifically AMPA receptors, play a crucial role in synaptic plasticity and neurotransmission.
- Previous studies indicated reduced GluR2 mRNA in the hippocampus of individuals with schizophrenia.
Purpose of the Study:
- To quantitatively assess GluR2 mRNA expression and its alternatively spliced isoforms (flip and flop) in the hippocampus of schizophrenic patients and controls.
- To investigate the correlation between GluR2 mRNA abundance and the encoded subunit levels.
- To explore the implications of altered GluR2 expression on AMPA receptor function in schizophrenia.
Main Methods:
- Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was employed to measure mRNA levels.
- Expression levels were normalized to cyclophilin mRNA to account for variations in RNA input.
- Statistical analyses were performed, controlling for potential confounding factors like brain pH and age.
Main Results:
- Schizophrenic patients exhibited significantly reduced expression of both GluR2 'flip' and 'flop' mRNA isoforms compared to controls.
- A disproportionately greater reduction in the 'flop' isoform resulted in an elevated flip:flop ratio in schizophrenics.
- A positive correlation was observed between GluR2 mRNA abundance and the levels of the encoded GluR2 subunit.
Conclusions:
- The study confirms reduced hippocampal GluR2 mRNA in schizophrenia and reveals a shift towards the 'flip' variant.
- These alterations suggest impaired signal transduction through hippocampal AMPA receptors due to both decreased GluR2 expression and altered subunit composition.
- The findings reinforce the hypothesis of glutamatergic dysfunction in schizophrenia, impacting AMPA receptor kinetics and neuronal signaling.