DIFFERENTIAL REGULATION OF THE EXPRESSION OF NERVE GROWTH-FACTOR, BRAIN-DERIVED NEUROTROPHIC FACTOR AND NEUROTROPHIN-3 MESSENGER-RNAS IN ADULT-RAT BRAIN AFTER INTRAHIPPOCAMPAL INJECTION OF QUINOLINIC ACID

Intrahippocampal injection of the endogenous excitotoxin quinolinic ac id (QUIN) induces seizures together with local, delayed neurodegenerat ion in specific cell layers. In situ hybridization histochemistry was used to study the spatio-temporal pattern of expression of neurotrophi ns (NTFs) after this treatment. As in other excitatory paradigms, nerv e growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRN A levels increased dramatically and transiently in dentate gyrus after the administration of 120 nmol of QUIN to the left hippocampus. BDNF, but not NGF, mRNA also increased in the hippocampal pyramidal cell la yer, mainly in the CA1 field. Neurotrophin-3 (NT3) mRNA levels decreas ed in dentate gyrus, practically disappeared around 12 h after the ins ult and returned to basal levels four days later. A very different pat tern of expression of NTFs was found locally: (a) upregulation of NGF and BDNF mRNAs expression was prevented in a spherical region of 1-2 m m diameter around the injection site, (b) a delayed increase in NT3 mR NA levels, beginning at 12 h and lasting for at least 4 days after the administration of QUIN, was found in the same region, in cell layers showing neurodegeneration. Pretreatment with the non-competitive NMDA antagonist MK-801 (2 mg/kg, 30 min before the insult), partially block ed the increase in both BDNF and NGF mRNAs, as well as the decrease in NT3, in the contralateral hippocampus. However, this treatment did no t prevent the QUIN-induced local downregulation of NGF and BDNF. Treat ment with the AMPA/kainate antagonist NBQX (30 mg/kg, 15 and 5 min bef ore, and 10 min after the insult) did not influence the effect of QUIN upon NGF or BDNF mRNA levels, although it partially prevented the hip pocampal contralateral decrease in NT3 mRNA. In conclusion, the presen t study strongly supports previous work concerning different regulatio n of BDNF/NGF respect to NT3 in seizure inducing paradigms. Moreover, the different and to some extent opposite regulation of NTFs in the hi ppocampal region contiguous to the injection site, respect to the rema ining hippocampus, suggests a differential regulation of NTFs in QUIN- induced neurodegenerative and seizural processes. Finally, our pharmac ological data, (i) show that the upregulation of NGF and BDNF mRNAs, i ndirectly induced by QUIN, is not mediated by AMPA receptors, and (ii) suggest other effects for QUIN, apart from the stimulation of NMDA re ceptors.