The excitatory ionotropic glutamate receptors N-methyl- d-aspartate (NMDA) and alpha-amino-3-hydro-5methyl-4-isoxazole propionic acid (AMPA) receptors, and the inhibitory gamma-aminobutyric acid (GABA) receptors are major regulators of synaptic transmission in the central nervous system. Glutamate receptors AMPA GluR2/3 and NMDA R2A: NR2A (NMDAepsilon1), and GABA(A) (GABA(A) Ralpha1) receptors were examined by immunohistochemistry in the cerebral cortex (frontal cortex) entorhinal cortex, hippocampus and cerebellar cortex in nine patients with sporadic Creutzfeldt-Jakob disease (CJD) and eight age-matched controls obtained 3-8 h after death. All patients with CJD showed methionine/methionine in codon 129 of the prion protein gene. Decreased GluR2/3 immunoreactivity was found in the frontal cortex, entorhinal cortex and Purkinje cells; reduced NMDAepsilon1 immunoreactivity was found in the frontal cortex, entorhinal cortex, and molecular and granular cell layers of the cerebellum. Decreased GluR2/3 and NMDAepsilon1 immunoreactivity was also observed in the molecular layer of the dentate gyrus, but not in the hippocampus proper in cases with hippocampal involvement. GABA(A) Ralpha1 expression was markedly decreased in the granular cell layer of the cerebellum in CJD. Decreased GluR2/3 and NMDAepsilon1 expression correlated with prion protein deposition, neuron loss and spongiform degeneration in the cerebral cortex in every case. However, reduced GluR2/3 immunoreactivity in Purkinje cells was apparently independent of these parameters. In contrast to ionotropic glutamate receptors, GABA(A) Ralpha1 immunoreactivity was moderately increased in the frontal cortex, entorhinal cortex and molecular layer of the cerebellum in CJD. The present results show marked and selective abnormalities in the expression of crucial neurotransmitter receptors in CJD, ionotropic glutamate receptors being more severely affected than ionotropic GABA receptors. These findings stress selective vulnerability of glutamate receptors versus GABA receptors in CJD.