Two important clinical observations about schizophrenics are not accounted for by most animal models: 1) typical onset of symptoms just after puberty, and 2) structural abnormalities in the hippocampal formation, possibly due to early developmental injury. A novel rat model of schizophrenic, in which neonatal rats receive excitotoxic lesions of ventral hippocampus (VH), yields rats which appear normal until puberty, but then exhibit behavioral abnormalities which model schizophrenic symptoms in humans. This model will be used to study the role of excitatory amino acid (EAA) transmitters in schizophrenia. An important role for EAAs in schizophrenia is indicated by reports that both EAA receptor expression and EAA levels are altered in schizophrenic brains and in rat brains following subchronic administration of antipsychotic drugs. Proposed studies will determine if changes in EAA receptors or levels accompany postpubertal onset of symptoms in VH-lesioned rats, focusing on medial prefrontal cortex and nucleus accumbens.
Aims are: 1) In vivo microdialysis will compare basal and K-stimulated EAA levels in VH- and sham-lesioned rats, 2) In situ hybridization histochemistry will be used to quantitatively examine mRNA levels for AMPA and NMDA receptor subunits in VH- and sham-lesioned rats. 3) Autoradiographic immunocytochemistry will examine the same subunits at the protein level. 4) Rats will be prescreened for response to novelty to correlate magnitude of behavioral and EAA abnormalities.
For Aims 1 -3, it will be determined whether any observed changes are normalized by subchronic haloperidol or clozapine. Results should provide information about the possibility that developmentally-induced abnormalities in EAA transmission contribute to schizophrenia.
| Stine, C D; Lu, W; Wolf, M E (2001) Expression of AMPA receptor flip and flop mRNAs in the nucleus accumbens and prefrontal cortex after neonatal ventral hippocampal lesions. Neuropsychopharmacology 24:253-66 |
