Elsevier

Biological Psychiatry

Volume 55, Issue 8, 15 April 2004, Pages 797-803
Biological Psychiatry

Original article
Altered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle

https://doi.org/10.1016/j.biopsych.2003.12.015Get rights and content

Abstract

Background

Survival and differentiation of neurons and the formation and maintenance of synapses in the cerebral cortex may be affected in schizophrenia. Since neurotrophins play an important role in these events, behavioral effects relevant to schizophrenia were investigated in rats that had compromised neurotrophin function during prefrontal cortical development.

Methods

Neonatal rat pups were injected into the developing prefrontal cortex with a depot preparation of p75 receptor antibody conjugated to saporin. Animals were tested for dopaminergic hyperresponsivity and prepulse inhibition of acoustic startle at 5 or 10 weeks. Neonatal and adult brain sections were examined for morphologic abnormality.

Results

Animals that received neonatal injections of p75 antibody conjugated to saporin showed significantly increased amphetamine-induced locomotion and rearing and impairment of prepulse inhibition of acoustic startle at 10 weeks of age but not at 5 weeks. Examination of adult brain sections revealed apparently normal structure, whereas neonatal brain sections showed apoptotic cells in the developing prefrontal cortex in pups that received p75 antibody conjugated to saporin.

Conclusions

Compromised p75 neurotrophin receptor function in the developing prefrontal cortex may be associated with the manifestation of adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition and therefore may be involved in the pathogenesis of schizophrenia.

Section snippets

Methods and materials

Sprague-Dawley rats were used throughout the study. The day of birth of pups was considered as day 0. Pups were weaned at day 21; thereafter, they were housed four per cage in plastic cages on a 12-hour on and 12-hour off light/dark cycle and had free access to food and water. All procedures were approved by the Institutional Animal Care Committee and are in compliance with the Canadian and National Institute of Health Guides for Care and Use of Laboratory Animals. Every effort was taken to

Results

Crystal violet stained sections of adult brains of animals at 11 weeks that received neonatal injections of p75 antibody conjugated to saporin showed no obvious structural lesion in the prefrontal cortex (Figure 1A, B). The morphologic appearance of the entorhinal cortex, striatum, nucleus accumbens, ventral pallidum, amygdala, hippocampus, thalamus, ventral tegmental area, or the pedunculopontine tegmental nucleus, areas implicated in the PPI or subcortical dopaminergic regulation, was

Discussion

The present data indicate that animals that received neonatal injection of p75 antibody conjugated to saporin into the developing prefrontal cortex show impaired PPI of acoustic startle and behavioral changes characteristic of adult-onset dopaminergic hyperresponsivity. This is the first evidence that interference with a neurotrophin receptor function during development leads to delayed manifestation of dopaminergic hyperresponsivity and impaired PPI, features characteristic of schizophrenia.

Acknowledgements

This research was supported by grants from the Ontario Mental Health Foundation (NR).

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