Elevated levels of kynurenic acid during gestation produce neurochemical, morphological, and cognitive deficits in adulthood: implications for schizophrenia

Neuropharmacology. 2015 Mar;90:33-41. doi: 10.1016/j.neuropharm.2014.10.017. Epub 2014 Nov 1.

Abstract

The levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs), are elevated in the brains of patients with schizophrenia (SZ). We reported that increases of brain KYNA in rats, through dietary exposure to its precursor kynurenine from embryonic day (ED)15 to postnatal day (PD) 21, result in neurochemical and cognitive deficits in adulthood. The present experiments focused on the effects of prenatal exposure to elevated kynurenine on measures of prefrontal excitability known to be impaired in SZ. Pregnant dams were fed a mash containing kynurenine (100 mg/day; progeny = EKYNs) from ED15 until ED22. Controls were fed an unadulterated mash (progeny = ECONs). The dietary loading procedure elevated maternal and fetal plasma kynurenine (2223% and 693% above controls, respectively) and increased fetal KYNA (forebrain; 500% above controls) on ED21. Elevations in forebrain KYNA disappeared after termination of the loading (PD2), but KYNA levels in the prefrontal cortex (PFC) were unexpectedly increased again when measured in adults (PD56-80; 75% above controls). We also observed changes in several markers of prefrontal excitability, including expression of the α7nAChR (22% and 17% reductions at PD2 and PD56-80), expression of mGluR2 (31% and 24% reductions at ED21 and PD56-80), dendritic spine density (11-14% decrease at PD56-80), subsensitive mesolimbic stimulation of glutamate release in PFC, and reversal/extra-dimensional shift deficits in the prefrontally-mediated set-shifting task. These results highlight the deleterious impact of elevated KYNA levels during sensitive periods of early development, which model the pathophysiological and cognitive deficits seen in SZ.

Keywords: Alpha7 nicotinic receptors; Glutamate; Kynurenic acid; Prefrontal cortex; Schizophrenia; Set-shifting.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Attention / drug effects
  • Attention / physiology
  • Brain / drug effects*
  • Brain / growth & development*
  • Brain / pathology
  • Brain / physiopathology
  • Cognition / drug effects*
  • Cognition / physiology
  • Dendritic Spines / drug effects
  • Dendritic Spines / pathology
  • Dendritic Spines / physiology
  • Diet
  • Female
  • Glutamic Acid / metabolism
  • Kynurenic Acid / metabolism
  • Kynurenine / blood
  • Kynurenine / toxicity*
  • Male
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • RNA, Messenger
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / metabolism
  • Reversal Learning / drug effects
  • Reversal Learning / physiology
  • Schizophrenia
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism

Substances

  • RNA, Messenger
  • Receptors, Metabotropic Glutamate
  • alpha7 Nicotinic Acetylcholine Receptor
  • metabotropic glutamate receptor 2
  • Kynurenine
  • Glutamic Acid
  • Kynurenic Acid