PT  - JOURNAL ARTICLE
AU  - Manickavasagon Alkondon
AU  - Edna F. R. Pereira
AU  - Ping Yu
AU  - Emerson Z. Arruda
AU  - Luis E. F. Almeida
AU  - Paolo Guidetti
AU  - William P. Fawcett
AU  - Michael T. Sapko
AU  - William R. Randall
AU  - Robert Schwarcz
AU  - Danilo A. Tagle
AU  - Edson X. Albuquerque
TI  - Targeted Deletion of the Kynurenine Aminotransferase II Gene Reveals a Critical Role of Endogenous Kynurenic Acid in the Regulation of Synaptic Transmission via <em>α</em>7 Nicotinic Receptors in the Hippocampus
AID  - 10.1523/JNEUROSCI.5631-03.2004
DP  - 2004 May 12
TA  - The Journal of Neuroscience
PG  - 4635--4648
VI  - 24
IP  - 19
4099  - http://www.jneurosci.org/content/24/19/4635.short
4100  - http://www.jneurosci.org/content/24/19/4635.full
SO  - J. Neurosci.2004 May 12; 24
AB  - It has been postulated that endogenous kynurenic acid (KYNA) modulates α7* nicotinic acetylcholine receptor (nAChR) and NMDA receptor activities in the brain.a To test this hypothesis, α7* nAChR and NMDA receptor functions were studied in mice with a targeted null mutation in the gene encoding kynurenine aminotransferase II (mKat-2-/- mice), an enzyme responsible for brain KYNA synthesis. At 21 postnatal days, mKat-2-/- mice had lower hippocampal KYNA levels and higher spontaneous locomotor activity than wild-type (WT) mice. At this age, α7* nAChR activity induced by exogenous application of agonists to CA1 stratum radiatum interneurons was ∼65% higher in mKat-2-/- than WT mice. Binding studies indicated that the enhanced receptor activity may not have resulted from an increase in α7* nAChR number. In 21-d-old mKat-2-/- mice, endogenous α7* nAChR activity in the hippocampus was also increased, leading to an enhancement of GABAergic activity impinging onto CA1 pyramidal neurons that could be reduced significantly by acute exposure to KYNA (100 nM). The activities of GABAA and NMDA receptors in the interneurons and of α3β4* nAChRs regulating glutamate release onto these neurons were comparable between mKat-2-/- and WT mice. By 60 d of age, KYNA levels and GABAergic transmission in the hippocampus and locomotor activity were similar between mKat-2-/- and WT mice. Our findings that α7* nAChRs are major targets for KYNA in the brain may provide insights into the pathophysiology of schizophrenia and Alzheimer's disease, disorders in which brain KYNA levels are increased and α7* nAChR functions are impaired.