Altered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle.
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.
Rajakumar
N
N
Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada.
Leung
L S
LS
Ma
J
J
Rajakumar
B
B
Rushlow
W
W
D000161:Acoustic Stimulation / Q000379:methods; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D006967:Hypersensitivity / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D037181:Lectins, C-Type; D009043:Motor Activity / Q000187:drug effects / Q000528:radiation effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D058580:Neurocan; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism* / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects
D000906:Antibodies; D011508:Chondroitin Sulfate Proteoglycans; D015259:Dopamine Agents; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins; D058580:Neurocan; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; C076817:NCAN protein, human; D002795:Choline O-Acetyltransferase; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003913:Dextroamphetamine; D004298:Dopamine