Neonatal perturbation of neurotrophic signaling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development

Abstract

Epidermal growth factor (EGF) and its structurally related proteins are implicated in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. There are EGF and EGF receptor abnormalities in both brain tissues and blood from schizophrenic patients. We administered EGF to neonatal rats to transiently perturb endogenous EGF receptor signaling and evaluated the neurobehavioral consequences. EGF-treatment-induced transient impairment in tyrosine hydroxylase expression. The animals grew normally, exhibited normal weight increase, glial growth, and gross brain structures, and later lost the tyrosine hydroxylase abnormality. During and after development, however, the rats began to display various behavioral abnormalities. Abnormal sensorimotor gating was apparent, as measured by deficits in prepulse inhibition of acoustic startle. Motor activity and social interaction scores of the EGF-treated animals were also impaired in adult rats, though not in earlier developmental stages. In parallel, there was a significant abnormality in dopamine metabolism in the brain stem of the adult animals. Gross learning ability appeared to be normal as measured by active avoidance. These behavioral alterations, which are often present in schizophrenic models, were ameliorated by subchronic treatment with clozapine. Although the molecular and/or physiologic background(s) of these behavioral abnormalities await further investigation, the results of the present experiment indicate that abnormal EGF receptor stimulation given during limited neonatal stages can result in severe and persistent cognitive/behavioral dysfunctions, which appear only in adulthood.

ErbB1 receptor ligands attenuate the expression of synaptic scaffolding proteins, GRIP1 and SAP97, in developing neocortex

“…It is noteworthy that a concentration of EGF in a sub-picomolar range (approximately 2 pM) was enough to reduce the PDZ protein levels. The concentration is much lower than those conventionally required for the high-affinity binding of EGF receptors (ErbB1; 100 pM) (Futamura et al, 2003). This suggests that particular heteromeric compositions of the ErbB receptors might contribute to this sensitivity (Jaulin-Bastard et al, 2001;Wong and Guillaud, 2004).…”

“…EGF was administered s.c. to neonatal rats. Administered EGF penetrated blood-brain barrier, leading to the phosphorylation of ErbB1 receptors in rat neocortex as indicated previously (Futamura et al, 2003) (Fig. 7A).…”

“…Additionally, immunohistochemical staining with antipan-PDZ antibodies revealed that EGF treatment inhibited the accumulation of anti-pan-PDZ immunoreactive puncta in vivo as observed in primary neocortical cultures, presumably suggesting the negative effects on postsynaptic development. Previous histologic examination verified normal brain structures in EGF-treated neonates and revealed that there is no apparent effect on astrocytes as determined by GFAP staining (Futamura et al, 2003). Given the basal levels of ErbB1 receptor phosphorylation in the neocortex, these results presumably implicate endogenous ErbB1 receptor ligands in selective development of post-synaptic structures containing various PDZ proteins.…”

“…Peripherally administered EGF penetrates the blood-brain barrier of neonatal rats and affects neurochemical markers in the brain (Futamura et al, 2003). Cytochrome c was used for control injections because it has similar chemical characteristics as EGF including its molecular weight and isoelectric point, but lacks the biological activity of EGF (Calamandrei and Alleva, 1989).…”

“…Since the blood-brain barrier has not yet been established in rat neonates, EGF penetrated into the brain and acted on developing neurons without affecting cell proliferation (Kleshcheva, 1988). Animals treated with EGF as neonates develop normally and acquire normal learning abilities, ruling out the possibility that EGF treatment grossly impairs normal brain development and functions (Kornblum et al, 1995;Futamura et al, 2003). Repeated daily administration of EGF specifically suppressed the expression of the PDZ proteins in the rat neocortex.…”