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.

Fig. 1.

Effects of L-KYN Administration on Fear Conditioning. Rats treated with L-KYN during adolescence exhibited comparable levels of freezing during training (A) and during the tone test session (C) compared with vehicle-treated control rats. In contrast, freezing was reduced in L-KYN-treated rats during the context test session (B). Freezing was defined as the absence of movement (except for respiration). During training, each rat was observed every 8 s during the 64-s period preceding the first trial (BL, baseline) and during the 64-s period after each trial (PS, postshock period). For the context test, the test period was broken up into 64-s epochs and rats were observed every 8 s. For the tone test session, rats were observed every 2 s during the tone presentation. Data are mean ± SE.

Fig. 2.

Effects of L-KYN Administration during Adolescence on Novel Object Recognition in Adulthood. The amount of time control rats and L-KYN-treated rats spent exploring the novel and familiar objects during the test session is shown in panel A. Panel B depicts the average discrimination ratios (±SEM) of each group, calculated as the time spent exploring the novel object divided by total time spent exploring both objects. A discrimination ratio of 0.5 indicates no discrimination between the novel and familiar objects, as indicated by the dotted line. Values significantly greater than 0.5 reflect successful discrimination, ie, rats spent more time exploring the novel vs. familiar object. Control rats, but not those treated with L-KYN during adolescence, discriminated between the novel and familiar objects indicating that object memory was impaired in L-KYN-treated rats. *P < .03.

Fig. 3.

L-KYN Administration during Adolescence Had No Effect on Locomotor Activity during the Habituation Session of the Novel Object Recognition Task. Data are mean ± SE.