The dipeptide N-acetylaspartylglutamate (NAAG) has been recently implicated in numerous neurological disorders. NAAG binds and stimulates group II metabotropic glutamate receptors producing a down-modulation of synaptic glutamate release. In the present immunohistochemical study, we compare the distribution of NAAG-containing (NAAGergic) neurons between the hippocampus of control and chronic epileptic rats obtained with the pilocarpine model of temporal lobe epilepsy. In the hippocampal formation, NAAGergic neurons comprise a subpopulation of GABAergic neurons. Examination by light microscopy revealed a significant reduction of NAAG-immunoreactive neurons in CA3 stratum oriens (35.8%) and CA1 stratum oriens (78.87%), stratum pyramidale (40%), and stratum radiatum (56.6%). Similar loss of NAAGergic neurons was observed in the subiculum characterized by 71.82% and 77.53% reduction in the stratum oriens and radiatum, respectively, when compared with controls. NAAGergic neurons in CA2 and dentate gyrus were apparently resistant to seizure-related cell loss but appeared more complex and exhibited numerous NAAG-positive puncta. Our findings indicate a selective vulnerability of NAAGergic neurons in temporal lobe epilepsy. © 2007 Elsevier B.V. All rights reserved.