Hippocampal mossy fiber long‐term depression in Grm2/3 double knockout mice

Lyon, Louisa; Borel, Mélodie; Carrión, Miriam; Kew, James N.C.; Corti, Corrado; Harrison, Paul J.; Burnet, Philip W.J.; Paulsen, Ole; Rodríguez‐Moreno, Antonio

doi:10.1002/syn.20923

Cited by 33 publications

(32 citation statements)

References 32 publications

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“…It is plausible that the reduced dopamine ‘tone’ reported here contributes to these findings. Whether it also underlies the arousal-dependent effect on spatial memory [10] or the impaired long-term depression [22] of the mice, is unknown. But it may be significant that the NAc is involved in motivation, reward and aversion [23,24].…”

Section: Discussionmentioning

confidence: 99%

Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice

et al. 2013

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BackgroundGroup II metabotropic glutamate receptors (mGlu2 and mGlu3, encoded by Grm2 and Grm3) have been the focus of attention as treatment targets for a number of psychiatric conditions. Double knockout mice lacking mGlu2 and mGlu3 (mGlu2/3−/−) show a subtle behavioural phenotype, being hypoactive under basal conditions and in response to amphetamine, and with a spatial memory deficit that depends on the arousal properties of the task. The neurochemical correlates of this profile are unknown. Here, we measured tissue levels of dopamine, 5-HT, noradrenaline and their metabolites in the striatum and frontal cortex of mGlu2/3−/− double knockout mice, using high performance liquid chromatography. We also measured the same parameters in mGlu2−/− and mGlu3−/− single knockout mice.ResultsmGlu2/3−/−mice had reduced dopamine levels in the striatum but not in frontal cortex, compared to wild-types. In a separate cohort we replicated this deficit and, using tissue punches, found it was more prominent in the nucleus accumbens than in dorsolateral striatum. Noradrenaline, 5-HT and their metabolites were not altered in the striatum of mGlu2/3−/− mice, although the noradrenaline metabolite MHPG was increased in the cortex. In mGlu2−/− and mGlu3−/− single knockout mice we found no difference in any monoamine or metabolite, in either brain region, compared to their wild-type littermates.ConclusionsGroup II metabotropic glutamate receptors impact upon striatal dopamine. The effect may contribute to the behavioural phenotype of mGlu2/3−/− mice. The lack of dopaminergic alterations in mGlu2−/− and mGlu3−/− single knockout mice reveals a degree of redundancy between the two receptors. The findings support the possibility that interactions between mGlu2/3 and dopamine may be relevant to the pathophysiology and therapy of schizophrenia and other disorders.

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Section: Discussionmentioning

confidence: 99%

Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice

et al. 2013

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“…Brains were taken from adult Grm3 −/− knockout mice, Grm2 −/− /3 −/− double knockout mice, and wild-type mice (Lyon et al, 2008, Lyon et al, 2011a, De Filippis et al, 2015), snap frozen, and stored at − 80 °C. For protein isolation, a small piece of frontal tissue was cut with a clean razor blade, weighed, and homogenised using membrane extraction buffer and a Dounce homogeniser on ice ( n = 3 adult female mice per genotype).…”

Section: Methodsmentioning

confidence: 99%

Metabotropic glutamate receptor 3 (mGlu3; mGluR3; GRM3) in schizophrenia: Antibody characterisation and a semi-quantitative western blot study

García-Bea

Walker

Hyde

et al. 2016

Schizophrenia Research

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BackgroundMetabotropic glutamate receptor 3 (mGlu3, mGluR3), encoded by GRM3, is a risk gene for schizophrenia and a therapeutic target. It is unclear whether expression of the receptor is altered in the disorder or related to GRM3 risk genotype. Antibodies used to date to assess mGlu3 in schizophrenia have not been well validated.ObjectiveTo characterise six commercially available anti-mGlu3 antibodies for use in human brain, and then conduct a semi-quantitative study of mGlu3 immunoreactivity in schizophrenia.MethodsAntibodies tested using Grm3−/− and Grm2−/−/3−/− mice and transfected HEK293T/17 cells. Western blotting on membrane protein isolated from superior temporal cortex of 70 patients with schizophrenia and 87 healthy comparison subjects, genotyped for GRM3 SNP rs10234440.ResultsOne (out of six) anti-mGlu3 antibodies was fully validated, a C-terminal antibody which detected monomeric (~ 100 kDa) and dimeric (~ 200 kDa) mGlu3. A second, N-terminal, antibody detected the 200 kDa band but also produced non-specific bands. Using the C-terminal antibody for western blotting in human brain, mGlu3 immunoreactivity was found to decline with age, and was affected by pH and post mortem interval. There were no differences in monomeric or dimeric mGlu3 immunoreactivity in schizophrenia or in relation to GRM3 genotype. The antibody was not suitable for immunohistochemistry.InterpretationThese data highlight the value of knockout mouse tissue for antibody validation, and the need for careful antibody characterisation. The schizophrenia data show that involvement of GRM3 in the disorder and its genetic risk architecture is not reflected in total membrane mGlu3 immunoreactivity in superior temporal cortex.

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“…Unexpectedly, two recent studies have called into question the induction mechanism underlying MF-LTD. Using more specific and potent group II mGluRs antagonists, as well as mGluR2/3 double knockout mice, these studies still observed presynaptic MF-LTD (Wostrack and Dietrich 2009;Lyon et al 2011). MF-LTD induced in mGluR2/3 double knockout mice was abolished by pharmacologically blocking kainate receptors (Lyon et al 2011), raising the intriguing possibility that these receptors, via a metabotropic action, could be involved in the induction of presynaptic MF-LTD (Negrete-Diaz et al 2007).…”

Section: Mossy Fiber To Ca3 Pyramidal Cell Synapse As a Model For Prementioning

confidence: 99%

Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses

Castillo

2011

Cold Spring Harbor Perspectives in Biology

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134

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Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTP and LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural circuits. A wide range of induction mechanisms has been identified, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identified across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTP and LTD can occur in vivo and likely mediate some forms of learning.A t several excitatory and inhibitory synapses, neuronal activity can trigger enduring increases or decreases in neurotransmitter release, thereby producing long-term potentiation (LTP) or long-term depression (LTD) of synaptic strength, respectively. In the last decade, many studies have revealed that these forms of plasticity are ubiquitously expressed in the mammalian brain, and accumulating evidence indicates that they may underlie behavioral adaptations occurring in vivo. These studies have also uncovered a wide range of induction mechanisms, which converge on the presynaptic terminal where an enduring modification in the neurotransmitter release process takes place. Interestingly, presynaptic forms of LTP/ LTD can coexist with classical forms of postsynaptic plasticity. Such diversity expands the dynamic range and repertoire by which neurons modify their synaptic connections. This review discusses mechanistic aspects of presynaptic LTP and LTD at both excitatory and inhibitory synapses in the mammalian brain, with an emphasis on recent findings. INDUCTION MECHANISMSAs illustrated in Figure 1, presynaptic LTP/LTD at both excitatory and inhibitory synapses can be induced in a homosynaptic or heterosynaptic manner, with induction occurring either entirely at the presynaptic terminal or requiring a retrograde messenger arising from the postsynaptic neuron. Each of these four induction

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Hippocampal mossy fiber long‐term depression in Grm2/3 double knockout mice

Cited by 33 publications

References 32 publications

Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice

Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice

Metabotropic glutamate receptor 3 (mGlu3; mGluR3; GRM3) in schizophrenia: Antibody characterisation and a semi-quantitative western blot study

Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses

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