Neonatal infection with neurotropic influenza A virus induces the kynurenine pathway in early life and disrupts sensorimotor gating in adult Tap1-/- mice

Abstract

Epidemiological studies suggest that early life infections may contribute to the development of neuropsychiatric disorders later in life. Experimental studies employing infections during neonatal life support this notion by reporting persistent changes in the behaviour of adult animals, including deficits in sensorimotor gating. We have previously described an induction of the kynurenine pathway in neonatal wild-type (WT) mice following a systemic infection with neurotropic influenza A/WSN/33 virus. Here, we use the same model of infection in both WT and Tap1-/- mice (expressing reduced levels of MHC class I) and study long-term effects of the infection on sensorimotor gating, as determined by measuring prepulse inhibition (PPI). Moreover, transcription of genes encoding enzymes in the kynurenine pathway and levels of kynurenic acid (KYNA), in the brain of Tap1-/- mice were investigated. In mice infected on postnatal day (P)3 or P4, the levels of several transcripts in the kynurenine pathway were altered at P7, P13 and P24. Transcripts encoding indoleamine-pyrrole 2,3-dioxygenase (IDO), degrading tryptophan in the first step of the kynurenine pathway were consistently up-regulated at all time-points investigated. The changes in transcript levels were accompanied by a transient elevation of KYNA in the brain of infected mice at P13. At age 5-6 months, neonatally infected Tap1-/-, but not WT, mice exhibited a reduction in PPI. The present data show that a neonatal infection targeting the brain can induce the kynurenine pathway and that such an infection can disrupt sensorimotor gating in adulthood in genetically vulnerable mice.

Fig. 1

Schematic diagram of the kynurenine pathway. Mouse gene symbols are given in parentheses.

Fig. 2

Levels of transcripts in brains of Tap1^−/− mice. Symbols (○, ●) represent individual mice. The levels of transcripts from the genes Indo (encoding IDO), Tdo2 (encoding TDO), Ccbl1 (encoding KAT1), Aadat (encoding KAT2), Ccbl2 (encoding KAT3), Got2 (encoding mitAAT), Kmo (encoding KMO), Kynu (encoding KYNU), Haao (encoding HAAO), and Qprt (encoding QPRT) in brains at (a) postnatal day (P)7, (b) P13, and (c) P24 following intraperitoneal injection with 2400 plaque-forming units of influenza A/WSN/33 virus (+) or phosphate-buffered saline (−) on P3 or P4. The levels of transcripts in virus-infected brains are relative to those observed in uninfected brains. The horizontal lines indicate median values (n = 8–11). * p < 0.05, ** p < 0.01, *** p < 0.001. Mann–Whitney U test.

Fig. 3

Levels of kynurenic acid (KYNA) in brains of Tap1^−/− mice at postnatal days (P)7, P13, P24 following intraperitoneal injection with 2400 plaque-forming units of influenza A/WSN/33 virus (+) or phosphate-buffered saline (−) on P3 or P4. Symbols (○, ●) represent individual mice. The horizontal lines indicate median values (n = 6–8). ** p < 0.01. Mann–Whitney U test.

Fig. 4

(a) Prepulse inhibition (PPI) and (b) startle magnitude in uninfected (n = 16) and influenza A/WSN/33 virus-infected (n = 12) Tap1^−/− mice at age 5–6 months, during the varied interstimulus interval (ISI) block of the startle session. ^# p < 0.05, main effect of virus infection on PPI during the varied ISI block (details of statistics in Results section). * p < 0.05, statistically different from respective uninfected mice, Tukey's post-hoc comparison. Data are presented as mean + s.e.m.

Fig. 5

Comparison of the effects of neonatal influenza in Tap1^−/− mice (left) and wild-type (WT) mice (right) on average PPI during the ISI block. Data represent the mean (+s.e.m.). * p < 0.05, significantly different from respective control. Data were compared across experiments by computing the effect size (Cohen's d): Tap1^−/− mice, d = 1.23; WT mice, d = 0.61. For details of statistics see Results section.