Neurotransmission in the hippocampus is modulated variously through presynaptic metabotropic glutamate receptors (mGluRs). To establish the precise localization of presynaptic mGluRs in the rat hippocampus, we used subtype-specific antibodies for eight mGluRs (mGluR1-mGluR8) for immunohistochemistry combined with lesioning of the three major hippocampal pathways: the perforant path, mossy fiber, and Schaffer collateral. Immunoreactivity for group II (mGluR2) and group III (mGluR4a, mGluR7a, mGluR7b, and mGluR8) mGluRs was predominantly localized to presynaptic elements, whereas that for group I mGluRs (mGluR1 and mGluR5) was localized to postsynaptic elements. The medial perforant path was strongly immunoreactive for mGluR2 and mGluR7a throughout the hippocampus, and the lateral perforant path was prominently immunoreactive for mGluR8 in the dentate gyrus and CA3 area. The mossy fiber was labeled for mGluR2, mGluR7a, and mGluR7b, whereas the Schaffer collateral was labeled only for mGluR7a. Electron microscopy further revealed the spatial segregation of group II and group III mGluRs within presynaptic elements. Immunolabeling for the group III receptors was predominantly observed in presynaptic active zones of asymmetrical and symmetrical synapses, whereas that for the group II receptor (mGluR2) was found in preterminal rather than terminal portions of axons. Target cell-specific segregation of receptors, first reported for mGluR7a , was also apparent for the other group III mGluRs, suggesting that transmitter release is differentially regulated by 2-amino-4-phosphonobutyrate-sensitive mGluRs in individual synapses on single axons according to the identity of postsynaptic neurons. Key words: metabotropic glutamate receptor; hippocampus; perforant path; mossy fiber; Schaffer collateral; axon terminal; preterminal; immunohistochemistry; lesionMetabotropic glutamate receptors (mGluRs) have various modulatory f unctions on neuronal excitability, transmitter release, and synaptic plasticity in the C NS (Pin and Duvoisin, 1995). These f unctions have been studied most extensively in the hippocampus because of its roles in learning and memory and of its architecture, which is compartmentalized well with the three major excitatory pathways: the perforant path, mossy fiber, and Schaffer collateral. The mGluRs consist of at least eight subtypes that are classified into three groups (Nakanishi and Masu, 1994;Pin and Duvoisin, 1995). Group I mGluRs (mGluR1/mGluR5) are selectively activated by 3,5-dihydroxyphenylglycine (DHPG) (Schoepp et al., 1994) and coupled to inositol phospholipid hydrolysis. On the other hand, group II mGluRs (mGluR2/ mGluR3) and group III mGluRs (mGluR4/mGluR6/mGluR7/ mGluR8), which are linked to inhibition of the cAM P cascade in receptor-transfected cell lines, are selectively activated by 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) (Hayashi et al., 1993) and 2-amino-4-phosphonobutyrate (L-AP4), respectively.Excitability of hippocampal neurons is modulated directly through group I mGluRs (Davies et...

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