Effects of L-kynurenine on fear conditioning may have implications for schizophrenia treatment

Dartmouth professor David Bucci, alumna Amy Chess, and Allison Landers ’09 recently published their work on the effects of L-kynurenine on contextual fear conditioning and context discrimination in rats in Behavioural Brain Research. L-kynurenine, a precursor of kyneurinic acid (KYNA), is a possible contributor to cognitive defects observed in schizophrenia.

KYNA is a gliotransmitter, a chemical released by glial cells to impact neuronal function. The findings from a series of three experiments supported the hypothesis that elevated KYNA concentration impairs contextual fear conditioning but spares cue-specific fear conditioning. 

 “We used aversive conditioning for its tight temporal resolution over phases of memory,” Professor Bucci explained. This conditioning consisted of delivering a mild foot shock paired with either an environment or a sound. The rats’ subsequent freezing response served as a measure of conditioned fear.

The experimental group was given L-kynurenine (L-KYN), shown to increase KYNA concentration, affecting α7 nicotinic acetylcholine receptors and NMDA receptors. During the initial training session, the control and experimental groups showed comparable amounts of post-shock freezing.

Researchers designed the first experiment to test the rats’ contextual fear and cue-specific fear by re-exposing the rats to the initial training environment or initial tone, respectively. As the researchers predicted, rats treated with L-KYN exhibited decreased freezing during the context test, while the control and experimental groups exhibited comparable freezing levels during the cue-specific test.

 To mimic impaired configural processing in schizophrenia, and to better explain the results of the first experiment, the second experiment encouraged the rats to use a configural learning strategy. Specifically, the experiment examined rats’ ability to distinguish between a shock and no-shock context using unified representations from multimodal sensory cues. While both groups learned the difference between the environments, the rats treated with L-KYN took longer than the control rats to make the differentiation.

 The third experiment expanded upon the second experiment by eliminating the possibility that L-KYN treated rats were learning via an elemental or cue-based strategy instead of the desired contextual strategy.

 These findings have helped redefine glia’s role in the nervous system and provide insight into possible schizophrenia treatments. Bucci explained, “Currently the two main drugs for schizophrenia, haldol and chlozapine, treat the hallucinations and paranoia but are very ineffective at treating the cognitive defects.” Future work can be done to intercede or block KYNA levels to aid cognitive function.           

 In addition, the researchers have collaborated with Dr. Alan Green, Chair of Psychiatry at Dartmouth Medical School, who studies the co-occurrence of drug abuse and schizophrenia. This work can help determine if KYNA elevation promotes substance abuse and if the increased prevalence of smoking noted among schizophrenia patients is a possible form of self-medication.

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