title: Exposure to kynurenic acid during adolescence produces memory deficits in adulthood.
abstract: The glia-derived molecule kynurenic acid (KYNA) is an antagonist of α7 nicotinic acetylcholine receptors and the glycine(B) binding site on n-methyl-d-aspartateglutamate receptors, both of which have critical roles in neural plasticity as well as learning and memory. KYNA levels are increased in the brains and cerebral spinal fluid of persons with schizophrenia, leading to the notion that changes in KYNA concentration might contribute to cognitive dysfunction associated with this disorder. Indeed, recent studies indicate that increasing endogenous KYNA concentration by administering l-kynurenine (L-KYN, the precursor of KYNA) impairs spatial as well as contextual learning and memory in adult rats. In the present study, rats were treated with L-KYN (100 mg/kg) throughout adolescence to increase endogenous KYNA concentration during this critical time in brain development. Rats were then tested drug-free as adults to test the hypothesis that exposure to elevated levels of KYNA during development may contribute to cognitive dysfunction later in life. Consistent with prior studies in which adult rats were treated acutely with L-KYN, juvenile rats exposed to increased KYNA concentration during adolescence exhibited deficits in contextual fear memory, but cue-specific fear memory was not impaired. In addition, rats treated with L-KYN as adolescents were impaired on a novel object recognition memory task when tested as adults. The memory deficits could not be explained by drug-induced changes in locomotor activity or shock sensitivity. Together, these findings add to the growing literature supporting the notion that exposure to increased concentration of KYNA may contribute to cognitive deficits typically observed in schizophrenia.
authors.affiliation: Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA.
authors.forename: Cynthia O
authors.initials: CO
authors.lastname: Akagbosu
authors.forename: Gretchen C
authors.initials: GC
authors.lastname: Evans
authors.forename: Danielle
authors.initials: D
authors.lastname: Gulick
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Suckow
authors.forename: David J
authors.initials: DJ
authors.lastname: Bucci
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D005239:Fear; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000009:adverse effects* / Q000378:metabolism; D007859:Learning Disabilities / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000378:metabolism; D009043:Motor Activity; D018733:Nicotinic Antagonists; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011978:Receptors, Nicotinic; D021641:Recognition, Psychology; D012559:Schizophrenia / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579165:Chrna7 protein, rat; D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007737:Kynurenine; D007736:Kynurenic Acid