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Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients
G W Mathern1, J K Pretorius, H I Kornblum
1Department of Neurology, University of California, USA.
Abstract:
This study was designed to determine whether hippocampal neuronal AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and NMDA (N-methyl-D-aspartate) mRNA levels were differentially increased in temporal lobe epilepsy patients compared with those measured in control tissue from non-seizure autopsies. Hippocampi from hippocampal sclerosis patients (n = 28) and temporal mass lesion cases (n = 12) were compared with those from the autopsies (n = 4), and studied for AMPA GluR1-3 and NMDAR1-2 mRNAs using semi-quantitative in situ hybridization, along with fascia dentata and Ammon's horn neuron densities. Compared with the autopsies, and without correction for neuron counts, the mass lesion cases with neuron densities similar to autopsies showed: (i) significantly increased NMDAR2 hybridization densities for fascia dentata granule cells; (ii) increased AMPA GluR3 mRNA densities for Ammon's horn pyramids; and (iii) similar or numerically increased mRNAs for all other subunits and hippocampal subfields. Compared with the autopsies, hippocampal sclerosis cases with decreased neuron densities showed: (i) significantly decreased AMPA GluR1-2 and NMDAR1-2 hybridization densities for Ammon's horn pyramids and (ii) similar or numerically decreased mRNAs for all other subunits and subfields. However, correcting for changes in neuron densities showed that hippocampal sclerosis patients had increased AMPA and NMDA mRNA levels per neuron compared with autopsies, and in the CA2 resistant sector GluR2 mRNA levels were numerically greater than autopsies and mass lesion cases. Furthermore, relative to autopsies both sclerosis and mass lesion hippocampi showed that, in the stratum granulosum, the greatest mRNA increases were in AMPA GluR1 and NMDAR2 compared with the other mRNAs. In chronic temporal lobe seizure patients these results indicate that mass lesion and sclerosis cases show differential increases in hippocampal AMPA and NMDA mRNA levels per neuron compared with autopsies, especially for AMPA GluR1 and NMDAR2 in fascia dentata granule cells. These findings support the hypothesis that temporal lobe seizures are associated with increased ionotropic glutamate receptor mRNA levels and alterations in receptor subunit composition that probably contribute to neuronal hyperexcitability, synchronization and seizure generation.
Insights
Temporal lobe epilepsy patients show increased alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor mRNA levels per neuron. These changes in ionotropic glutamate receptors likely contribute to hyperexcitability and seizure generation.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- Temporal lobe epilepsy (TLE) is characterized by recurrent seizures originating in the temporal lobe.
- Ionotropic glutamate receptors, including AMPA and NMDA receptors, play crucial roles in synaptic transmission and neuronal excitability.
- Alterations in glutamate receptor expression are implicated in the pathophysiology of epilepsy.
Purpose of the Study:
- To investigate differential changes in hippocampal alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor mRNA levels in TLE patients.
- To compare mRNA levels between TLE subtypes (hippocampal sclerosis and temporal mass lesions) and control autopsy tissue.
Main Methods:
- Semi-quantitative in situ hybridization was used to analyze AMPA GluR1-3 and NMDA NMDAR1-2 mRNA expression in hippocampal subfields.
- Neuron densities in the fascia dentata and Ammon's horn were quantified.
- mRNA levels were compared between autopsy controls, hippocampal sclerosis cases (n=28), and temporal mass lesion cases (n=12).
Main Results:
- Mass lesion cases showed increased NMDAR2 and AMPA GluR3 mRNA densities, particularly in fascia dentata granule cells and Ammon's horn pyramids, respectively.
- Hippocampal sclerosis cases exhibited decreased AMPA GluR1-2 and NMDAR1-2 mRNA densities in Ammon's horn pyramids before neuronal density correction.
- After correcting for neuron loss, hippocampal sclerosis patients displayed increased AMPA and NMDA mRNA levels per neuron, with notable increases in AMPA GluR1 and NMDAR2 in the stratum granulosum.
Conclusions:
- TLE, encompassing both mass lesion and sclerosis subtypes, is associated with differential increases in hippocampal ionotropic glutamate receptor mRNA levels per neuron.
- Specific subunits, notably AMPA GluR1 and NMDAR2, show the most significant increases in fascia dentata granule cells.
- These findings support the hypothesis that altered glutamate receptor expression contributes to neuronal hyperexcitability and seizure generation in TLE.