The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood-brain barrier of neonatal rats: a critical period for efficacy.
Proinflammatory cytokines circulating in the periphery of early postnatal animals exert marked influences on their subsequent cognitive and behavioral traits and are therefore implicated in developmental psychiatric diseases such as schizophrenia. Here we examined the relationship between the permeability of the blood-brain barrier to interleukin-1 alpha (IL-1 alpha) in neonatal and juvenile rats and their later behavioral performance. Following s.c. injection of IL-1 alpha into rat neonates, IL-1 alpha immunoreactivity was first detected in the choroid plexus, brain microvessels, and olfactory cortex, and later diffused to many brain regions such as neocortex and hippocampus. In agreement, IL-1 alpha administration to the periphery resulted in a marked increase in brain IL-1 alpha content of neonates. Repeatedly injecting IL-1 alpha to neonates triggered astrocyte proliferation and microglial activation, followed by behavioral abnormalities in startle response and putative prepulse inhibition at the adult stage. Analysis of covariance with a covariate of startle amplitude suggested that IL-1 alpha administration may influence prepulse inhibition. However, adult rats treated with IL-1 alpha as neonates exhibited normal learning ability as measured by contextual fear conditioning, two-way passive shock avoidance, and a radial maze task and had no apparent sign of structural abnormality in the brain. In comparison, when IL-1 alpha was administered to juveniles, the blood-brain barrier permeation was limited. The increases in brain IL-1 alpha content and immunoreactivity were less pronounced following IL-1 alpha administration and behavioral abnormalities were not manifested at the adult stage. During early development, therefore, circulating IL-1 alpha efficiently crosses the blood-brain barrier to induce inflammatory reactions in the brain and influences later behavioral traits.
Tohmi
M
M
Division of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Tsuda
N
N
Zheng
Y
Y
Mizuno
M
M
Sotoyama
H
H
Shibuya
M
M
Kawamura
M
M
Kakita
A
A
Takahashi
H
H
Nawa
H
H
D000161:Acoustic Stimulation / Q000379:methods; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D003423:Critical Period, Psychological; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000503:physiopathology; D053582:Interleukin-1alpha / Q000008:administration & dosage* / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors
D053582:Interleukin-1alpha; D009419:Nerve Tissue Proteins