Original articleAltered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle
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).
References (85)
Trophic factors and neuronal survival
Neuron
(1989)- et al.
Autoradiographic localization of dopamine D1 and D2 receptors in rat nucleus accumbensResistance to differential rearing conditions
Neuroscience
(1991) - et al.
Critical periods during sensory development
Curr Opin Neurobiol
(2000) Neurotrophins and activity-dependent development of the neocortex
Curr Opin Neurobiol
(1996)- et al.
Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia
Schizophr Res
(2001) - et al.
Blockade of endogenous ligands of trkB inhibits formation of ocular dominance columns
Neuron
(1997) - et al.
Effects of systemic and intracranial amphetamine injections on behaviour in the open fieldA detailed analysis
Pharmcol Biochem Behav
(1987) - et al.
Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor
Mol Cell Neurosci
(1997) - et al.
The action of neurotrophins in the development and plasticity of the visual cortex
Prog Neurobiol
(1996) - et al.
Dendritic spine hypoplasticity and down regulation of reelin and GABAergic tone in schizophrenia vulnerability
Neurobiol Dis
(2001)
Differential patterns of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNA and protein levels in developing regions of rat brain
Neuroscience
On the clinical and cognitive meaning of impaired sensorimotor gating in schizophrenia
Psychiatry Res
Limbic pathology in schizophreniaThe entorhinal region—a morphometric study
Biol Psychiatry
Simultaneous expression of brain-derived neurotrophic factor and neurotrophin-3 in Cajal-Retzius, subplate and ventricular progenitor cells during early development stages of the rat cerebral cortex
Neuroscience
Dopaminergic and serotonergic function following isolation rearing in ratsStudy of behavioural responses and postmortem and in vivo neurochemistry
Pharmcol Biochem Behav
Neurotrophin signal transduction in the nervous system
Curr Opin Neurobiol
Dopamine D(2) receptors and their role in atypical antipsychotic actionStill necessary and may even be sufficient
Biol Psychiatry
Disruption of prepulse inhibition of startle reflex in a neurodevelopmental model of schizophreniaReversal by clozapine, olanzapine and risperidone but not by haloperidol
Neuropsychopharmacology
Neurotrophins regulate dendritic growth in developing visual cortex
Neuron
How do thalamic axons find their way to the cortex?
Trends Neurosci
Impaired prepulse inhibition of acoustic startle in schizophrenia
Biol Psychiatry
Trk receptorsMediators of neurotrophin action
Curr Opin Neurobiol
Role of neurotrophins in cholinergic-neurone function in the adult and aged CNS
Trends Neurosci
The reduced neuropil hypothesisA circuit based model of schizophrenia
Biol Psychiatry
Lesions of the cholinergic nuclei in the rat basal forebrainExcitotoxins vs. an immunotoxin
Life Sci
From neuropathology to neurodevelopment
Lancet
Increased baseline occupancy of D2 receptors by dopamine in schizophrenia
Proc Natl Acad Sci U S A
Regulation of neurotrophin receptors during the maturation of the mammalian visual system
J Neurosci
The subplate, a transient neocortical structureIts role in the development of connections between thalamus and cortex
Annu Rev Neurosci
Nerve growth factor receptor immunoreactivity is transiently associated with the subplate neurons of the mammalian cerebral cortex
Proc Natl Acad Sci U S A
Structural and functional properties of the TRK family of neurotrophin receptors
Ann N Y Acad Sci
Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics
Arch Gen Psychiatry
Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients
Arch Gen Psychiatry
Reduced neuronal size in posterior hippocampus of schizophrenic patients
Schizophr Bull
Prestimulus effects on human startle reflex in normals and schizophrenics
Psychophysiology
Gating and habituation of the startle reflex in schizophrenic patients
Arch Gen Psychiatry
Symptom correlates of prepulse inhibition deficits in male schizophrenic patients
Am J Psychiatry
Prepulse inhibition of the acoustic startle response of rats is reduced by 6-hydroxydopamine lesions of the medial prefrontal cortex
Psychopharmacology
Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon
Arch Gen Psychiatry
Growth and targeting of subplate axons and establishment of major cortical pathways
J Neurosci
A novel p75NTR signaling pathway promotes survival, not death, of immunopurified neocortical subplate neurons
J Neurosci
Cell loss in the hippocampus of schizophrenics
Eur Arch Psychiatry Neurol Sci
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