GABA(A) receptor subunit expression changes in the human Alzheimers disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA type A receptors (GABA(A) Rs) are severely affected in Alzheimers disease (AD). However, the distribution and subunit composition of GABA(A) Rs in the AD brain are not well understood. This is the first comprehensive study to show brain region- and cell layer-specific alterations in the expression of the GABA(A) R subunits alpha1-3, alpha5, beta1-3 and gamma2 in the human AD hippocampus, entorhinal cortex and superior temporal gyrus. In late-stage AD tissue samples using immunohistochemistry we found significant alteration of all investigated GABA(A) Rs subunits except for alpha3 and beta1 that were well preserved. The most prominent changes include an increase in GABA(A) R alpha1 expression associated with AD in all layers of the CA3 region, in the stratum (str.) granulare and hilus of the dentate gyrus. We found a significant increase in GABA(A) R alpha2 expression in the str. oriens of the CA1-3, str. radiatum of the CA2,3 and decrease in the str. pyramidale of the CA1 region in AD cases. In AD there was a significant increase in GABA(A) R alpha5 subunit expression in str. pyramidale, str. oriens of the CA1 region and decrease in the superior temporal gyrus. We also found a significant decrease in the GABA(A) R beta3 subunit immunoreactivity in the str. oriens of the CA2, str. granulare and str. moleculare of the dentate gyrus. In conclusion, these findings indicate that the expression of the GABA(A) R subunits shows brain region- and layer-specific alterations in AD, and these changes could significantly influence and alter GABA(A) R function in the disease. Cover Image for this issue: doi: 10.1111 jnc.14179.Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA type A receptors (GABA(A) Rs) are severely affected in Alzheimers disease (AD). However, the distribution and subunit composition of GABA(A) Rs in the AD brain are not well understood. This is the first comprehensive study to show brain region- and cell layer-specific alterations in the expression of the GABA(A) R subunits alpha1-3, alpha5, beta1-3 and gamma2 in the human AD hippocampus, entorhinal cortex and superior temporal gyrus. In late-stage AD tissue samples using immunohistochemistry we found significant alteration of all investigated GABA(A) Rs subunits except for alpha3 and beta1 that were well preserved. The most prominent changes include an increase in GABA(A) R alpha1 expression associated with AD in all layers of the CA3 region, in the stratum (str.) granulare and hilus of the dentate gyrus. We found a significant increase in GABA(A) R alpha2 expression in the str. oriens of the CA1-3, str. radiatum of the CA2,3 and decrease in the str. pyramidale of the CA1 region in AD cases. In AD there was a significant increase in GABA(A) R alpha5 subunit expression in str. pyramidale, str. oriens of the CA1 region and decrease in the superior temporal gyrus. We also found a significant decrease in the GABA(A) R beta3 subunit immunoreactivity in the str. oriens of the CA2, str. granulare and str. moleculare of the dentate gyrus. In conclusion, these findings indicate that the expression of the GABA(A) R subunits shows brain region- and layer-specific alterations in AD, and these changes could significantly influence and alter GABA(A) R function in the disease. Cover Image for this issue: doi: 10.1111 jnc.14179.