No abstract

It has been postulated that endogenous kynurenic acid (KYNA) modulates ␣7* nicotinic acetylcholine receptor (nAChR) and NMDA receptor activities in the brain.a To test this hypothesis, ␣7* 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, ␣7* nAChR activity induced by exogenous application of agonists to CA1 stratum radiatum interneurons was ϳ65% higher in mKat-2 ؊/؊ than WT mice. Binding studies indicated that the enhanced receptor activity may not have resulted from an increase in ␣7* nAChR number. In 21-d-old mKat-2 ؊/؊ mice, endogenous ␣7* 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 GABA A and NMDA receptors in the interneurons and of ␣3␤4* 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 ␣7* 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 ␣7* nAChR functions are impaired.

These findings support the hypotheses that the nicotinic cholinergic system modulates social and repetitive behaviors and may be a therapeutic target to treat behavior deficits in ASD. Further, the BTBR mouse may be valuable for investigations of the role of nAChRs in social deficits and repetitive behavior.

Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5–6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low-affinity neurotrophin receptor, p75NTR, doubled. Of the nine 5′-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development.