Impairment of Hippocampal Mossy Fiber LTD in Mice Lacking mGluR2

Yokoi, Mineto; Kobayashi, Katsunori; Manabe, Toshiya; Takahashi, Tomoyuki; Sakaguchi, Isako; Katsuura, Goro; Shigemoto, Ryuichi; Ohishi, Hitoshi; Nomura, Sakashi; Nakamura, Kenji; Nakao, Kazuki; Katsuki, Motoya; Nakanishi, Shigetada

doi:10.1126/science.273.5275.645

Cited by 320 publications

(252 citation statements)

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“…In pup and adult rats, status epilepticus induces a reduction in expression of mGluR2 receptor mRNA in granule cells of the dentate gyrus. mGluR2 is localized to the preterminal zone at mossy fiber3 CA3 synapses Yokoi et al, 1996). Thus, downregulation of mGluR2 would be expected to result in enhanced glutamate release at mossy fiber3pyramidal CA3 synapses, thereby promoting hyperexcitation (see below).…”

Section: Discussionmentioning

confidence: 99%

“…Immunolabeling indicates localization of mGluR2 to presynaptic mossy fiber terminals, where it is postulated to mediate inhibition of glutamate release by a heterosynaptic mechanism Yokoi et al, 1996). Reduction in mGluR2 receptor expression after status epilepticus could thus lead to reduced inhibition of glutamate release, thereby promoting the hyperexcitation associated with severe limbic seizures.…”

Section: Significance Of Downregulation Of Mglur2 and Upregulation Ofmentioning

confidence: 99%

“…Immunoelectron microscopy indicates localization of mGluR2 protein at the preterminal zone of mossy fibers, where it is postulated to mediate inhibition of glutamate release Yokoi et al, 1996). mGluR4 is expressed prominently in the enthorinal cortex and cerebellum and at low levels in the hippocampal CA2, where it is thought to mediate heterosynaptic inhibition of glutamate release at pyramidal axon terminals Bradley et al, 1996;Kinoshita et al, 1996) …”

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confidence: 99%

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Status Epilepticus-Induced Alterations in Metabotropic Glutamate Receptor Expression in Young and Adult Rats

et al. 1997

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In adult rats, kainic acid induces status epilepticus and delayed, selective cell loss of pyramidal neurons in the hippocampal CA3. In pup rats, kainate induces status epilepticus but not the accompanying neuronal cell death. The precise mechanisms underlying this age-dependent vulnerability to seizure-induced cell death are not understood. Metabotropic glutamate receptors (mGluRs) are developmentally and spatially regulated throughout the hippocampus and are implicated in seizureinduced damage. In the present study we used in situ hybridization to examine possible changes in mGluR expression at the level of the hippocampus after status epilepticus in postnatal day 10 (P10) pup and adult (P40) rats. Status epilepticus did not alter expression of mGluR1, mGluR3, or mGluR5 mRNAs. In pup and adult rats, status epilepticus induced a reduction in expression of mGluR2 mRNA in granule cells of the dentate gyrus. This change could lead to augmented glutamate release at mossy fiber synapses on CA3 pyramidal cells and thereby promote hyperexcitation. In pup but not adult rats, mGluR4 mRNA expression was enhanced in CA3 pyramidal neurons. Upregulation of presynaptic mGluR4 in pup CA3 neurons could lead to reduced transmitter release from CA3 axons, including recurrent collaterals, thereby reducing vulnerability of neonatal CA3 neurons to seizure-induced damage. These findings indicate that status epilepticus affects mGluR expression in a gene-and cell-specific manner, and that these changes vary with the developmental stage.

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Section: Discussionmentioning

confidence: 99%

Section: Significance Of Downregulation Of Mglur2 and Upregulation Ofmentioning

confidence: 99%

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confidence: 99%

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Status Epilepticus-Induced Alterations in Metabotropic Glutamate Receptor Expression in Young and Adult Rats

et al. 1997

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“…This may help to explain why LY354740 suppressed only EPM-induced, but not basal neuronal activity in the CA3 pyramidal cell layer. Moreover, electrophysiological recordings on hippocampal slices from mGlu2 receptor knockout mice demonstrated that mGlu2 receptors are not required for the basal synaptic transmission at the mossy fiber-CA3 synapse (Yokoi et al, 1996). Intra-amygdaloid circuitry processes adversive information and regulates behavioral, autonomic, and neuroendocrine responses to stress/fear stimuli through the central nucleus, the main output region of the amygdala (Sun and Cassell, 1993;Davis et al, 1994;Pitkanen et al, 1997).…”

Section: Central C-fos After Anxiolytic Ly354740mentioning

confidence: 99%

Anxiolytic Activity of the MGLU2/3 Receptor Agonist LY354740 on the Elevated Plus Maze is Associated with the Suppression of Stress-Induced c-Fos in the Hippocampus and Increases in c-Fos Induction in Several Other Stress-Sensitive Brain Regions

Lindén

Greene

Bergeron

et al. 2003

Neuropsychopharmacol

100

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LY354740 is a potent and selective agonist for group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3 receptors, with anxiolytic activity in several animal models of anxiety, including the elevated plus maze (EPM) test. Here, we studied neuronal activation in mouse brain after EPM exposure in saline-and LY354740-treated mice using c-Fos immunoreactivity as a marker. The effect of LY354740 on c-Fos expression was also studied in cage control (no EPM) mice. Pretreatment with LY354740 (20 mg/kg, s.c.) produced robust anxiolytic behavior on the EPM. LY354740 administration decreased EPM-induced increases in c-Fos expression in the CA3 of the hippocampus, while having no significant effects on basal c-Fos expression in the hippocampus. LY354740 administration significantly increased c-Fos expression in specific limbic regions, including the lateral division of the central nucleus of the amygdala (CeL), lateral parabrachial nucleus, locus coeruleus, and Edinger-Westphal nucleus, whether or not animals were exposed to the EPM. Moreover, LY354740 administration per se significantly increased c-Fos expression in regions processing sensory information, including the paraventricular and lateral geniculate nucleus of the thalamus as well as the nucleus of the optic tract and superior colliculus. In particular, the suppression of fear-evoked neuronal activity in the hippocampus and drug-induced increases in neuronal activation in the CeL have been previously linked to the anxiolytic effects of clinically effective drugs such as benzodiazepines, and thus may contribute to anxiolytic actions of LY354740 in animal models and human anxiety patients.

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“…mGluR2 activation has previously been implicated in the induction of LTD at hippocampal mossy fiber-CA3 synapses (20,21). We therefore sought to determine whether constitutively active G␣ i2 expression also affected the induction of this persistent form of synaptic depression.…”

Section: Constitutively Active G␣i2 Enhances Ltd At Mossy Fiber-ca3 Smentioning

confidence: 99%

mGluR2 acts through inhibitory Gα subunits to regulate transmission and long-term plasticity at hippocampal mossy fiber-CA3 synapses

Nicholls¹,

Zhang²,

Bailey

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Presynaptic inhibitory G protein-coupled receptors play a critical role in regulating transmission at a number of synapses in the central and peripheral nervous system. We generated transgenic mice that express a constitutively active form of an inhibitory G␣ subunit to examine the molecular mechanisms underlying the actions of one such receptor, metabotropic glutamate receptor (mGluR) 2, at mossy fiber-CA3 synapses in the hippocampus. mGluR2 participates in at least three types of mossy fiber synaptic plasticity, (i) transient suppression of synaptic transmission, (ii) long-term depression (LTD), and (iii) inhibition of long-term potentiation (LTP), and we find that inhibitory G␣ signaling is sufficient to account for the actions of mGluR2 in each. The fact that constitutively active G␣ i2 occludes the transient suppression of synaptic transmission by mGluR2, while enhancing LTD, suggests further that these two forms of plasticity are expressed via different mechanisms. In addition, the LTP deficit observed in constitutively active G␣ i2-expressing mice suggests that mGluR2 activation may serve as a metaplastic switch to permit the induction of LTD by inhibiting LTP.O ne important mechanism whereby neuronal activity is controlled is through the action of presynaptic inhibitory G protein-coupled receptors (1, 2). One member of this group is the metabotropic glutamate receptor, mGluR2, which is present at mossy fiber-CA3 pyramidal cell synapses. Here, mGluR2s are localized perisynaptically near presynaptic terminals (3, 4), where they are thought to function as autoreceptors to suppress transmission in response to excess glutamate release. Pharmacological and genetic manipulations have shown that mGluR2s participate in at least three types of synaptic plasticity: (i) a transient suppression of synaptic transmission that occurs in response to receptor activation, (ii) a persistent form of synaptic depression requiring both mGluR2 activation and presynaptic calcium influx (long-term depression, LTD), and (iii) mGluR2-mediated inhibition of long-term potentiation (LTP) (5, 6).The relationship among these forms of mossy fiber-CA3 synaptic plasticity and the mechanism of mGluR2 involvement in each is not completely clear. Does the involvement of mGluR2 in both transient and persistent synaptic depression reflect a common mechanism, such that the persistent form merely results from a stabilization of the transient form, or does mGluR2 participate in these two processes via independent mechanisms? Similarly, does the inhibition of LTP by group II mGluR activation reflect opposing actions on a common effector pathway for depression and potentiation, or a permissive role for mGluR2 in inducing LTD by blocking LTP? We have begun to address these questions by exploring the signaling pathway downstream of mGluR2 using transgenic mice that express a constitutively active form of G␣ i2 . We find that the effects of mGluR2 on mossy fiber synaptic plasticity can be accounted for by the actions of inhibitory G␣ subunits. However,...

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Impairment of Hippocampal Mossy Fiber LTD in Mice Lacking mGluR2

Cited by 320 publications

References 23 publications

Status Epilepticus-Induced Alterations in Metabotropic Glutamate Receptor Expression in Young and Adult Rats

Status Epilepticus-Induced Alterations in Metabotropic Glutamate Receptor Expression in Young and Adult Rats

Anxiolytic Activity of the MGLU2/3 Receptor Agonist LY354740 on the Elevated Plus Maze is Associated with the Suppression of Stress-Induced c-Fos in the Hippocampus and Increases in c-Fos Induction in Several Other Stress-Sensitive Brain Regions

mGluR2 acts through inhibitory Gα subunits to regulate transmission and long-term plasticity at hippocampal mossy fiber-CA3 synapses

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