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Modulation of lateral perforant path excitatory responses by metabotropic glutamate 8 (mGlu8) receptors
Jin Zhai1, Ming Ting Tian, Yi Wang
1Neuroscience Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Abstract:
The contribution of metabotropic glutamate 8 (mGlu8) receptors to modulation of medial and lateral perforant path (MPP and LPP) inputs to the dentate gyrus was investigated using electrophysiological recording of field excitatory postsynaptic potentials (fEPSPs) from hippocampal slices taken from wild-type and mGlu8 receptor knockout animals. Application of the selective group III mGlu receptor agonist, L-AP4 (1-100 microM), reduced fEPSPs evoked by LPP, but not MPP stimulation in wild-type slices in a concentration-dependent manner (EC(50) = 4.7 microM). The selective mGlu8 receptor agonist, DCPG (1-30 microM) also suppressed LPP fEPSPs with an EC(50) value of 3.1 microM. The L-AP4-induced reduction in LPP fEPSPs could be blocked by the group III antagonist, MSOP (100 microM) in wild-type slices and was eliminated in mGlu8 receptor-deficient slices. Additional experiments showed that MPP fEPSPs were suppressed by the group II agonist, LY379268 (0.01-3 microM) in control slices (EC(50) = 153.1 nM); an effect that was not altered in mGlu8 receptor knockout slices (EC(50) = 153.8 nM). In addition, LY379268 had little effect on fEPSPs evoked by LPP stimulation in mGlu8 receptor-deficient slices. In conjunction with recent receptor localization studies, these results suggest that the mGlu8 receptors serve as autoreceptors on LPP afferents to the dentate gyrus.
Insights
Metabotropic glutamate 8 (mGlu8) receptors act as autoreceptors on lateral perforant path (LPP) afferents. These mGlu8 receptors modulate LPP inputs to the dentate gyrus, influencing synaptic transmission.
Area of Science:
- Neuroscience
- Receptor Pharmacology
- Synaptic Plasticity
Background:
- Metabotropic glutamate receptors (mGluRs) are crucial for modulating neuronal excitability and synaptic transmission.
- The specific role of the metabotropic glutamate 8 (mGlu8) receptor in regulating hippocampal circuitry remains incompletely understood.
- The perforant path, comprising medial (MPP) and lateral (LPP) pathways, provides major excitatory input to the dentate gyrus.
Purpose of the Study:
- To investigate the contribution of mGlu8 receptors to the modulation of MPP and LPP inputs to the dentate gyrus.
- To elucidate the specific roles of mGlu8 receptors in synaptic plasticity within the hippocampal formation.
Main Methods:
- Electrophysiological recording of field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices.
- Utilized wild-type and mGlu8 receptor knockout (KO) animal models.
- Administered selective group II and group III mGlu receptor agonists (LY379268, L-AP4, DCPG) and a group III antagonist (MSOP).
Main Results:
- Group III mGlu receptor agonists (L-AP4, DCPG) selectively suppressed LPP-evoked fEPSPs in wild-type slices, an effect absent in mGlu8 KO slices.
- MPP-evoked fEPSPs were suppressed by the group II agonist LY379268 in both wild-type and mGlu8 KO slices, indicating mGlu8 independence.
- LY379268 showed minimal effect on LPP fEPSPs in mGlu8 KO slices.
Conclusions:
- The findings strongly suggest that mGlu8 receptors function as autoreceptors on LPP afferents innervating the dentate gyrus.
- mGlu8 receptors play a specific role in regulating LPP input, distinct from MPP input modulation.
- This study provides critical insights into the differential regulation of hippocampal synaptic pathways by specific mGluR subtypes.