Expression of AMPA Receptor Flip and Flop mRNAs in the Nucleus Accumbens and Prefrontal Cortex after Neonatal Ventral Hippocampal Lesions

Abstract

Many lines of evidence implicate dysfunctional excitatory amino acid (EAA) transmission in schizophrenia. The present study examined α-amino-3-hydroxy-5-methylisoxazole- 4-priopionate (AMPA) receptor expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using a rat model of schizophrenia in which excitotoxic lesions of ventral hippocampus (VH) on postnatal day (PD) 7 lead to the postpubertal emergence of behavioral abnormalities that resemble schizophrenic symptoms. In situ hybridization histochemistry with 35S-labeled oligonucleotide probes was used to quantify mRNA levels for GluR1-3 flip and flop variants at prepubertal and postpubertal time-points (PD 35 and 60, respectively). Comparisons of PD 35 and PD 60 groups suggested that there may be changes in the relative expression of flip and flop isoforms during normal development. The most pronounced change was an apparent increase in the flip/flop ratio for GluR1 from PD 35 to PD 60 in both the PFC and the NAc. Neonatal VH lesions did not significantly alter GluR1-3 flip and flop mRNA levels in the NAc at either time-point. However, in the PFC, GluR3 flop mRNA levels were significantly decreased in lesioned rats at PD 60. AMPA receptors incorporating flop variants exhibit faster desensitization, so a shift towards flip incorporation might lead to increased neuronal excitability in the PFC, thereby influencing subcortical DA systems regulated by PFC efferents. In summary, an early developmental injury can predispose rats to abnormal development of EAA transmission in the PFC. This may contribute to the postpubertal onset of symptoms after neonatal VH lesions. [Neuropshychopharmacology 24:253–266, 2001]