Fractionation of Spatial Memory in GRM2/3 (mGlu2/mGlu3) Double Knockout Mice Reveals a Role for Group II Metabotropic Glutamate Receptors at the Interface Between Arousal and Cognition

Lyon, Louisa; Burnet, Philip W.J.; Jnc., Kew; Corti, Corrado; Jnp., Rawlins; Lane, Tracy; Filippis, Bianca De; Harrison, Paul J.; Bannerman, David M.

doi:10.1038/npp.2011.145

Cited by 57 publications

(76 citation statements)

References 68 publications

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“…Similarly, beta-NAcetylaspartylglutamate (b-NAAG) that acts as a mGluR3 antagonist significantly inhibited LTD. NAAG, a mGluR3 agonist, was found to impair the expression of LTP. More recently, mGluR2/3 double knock out mice were found to be impaired on appetitively motivated spatial reference and working memory tasks, and on a spatial novelty preference task that relies on the animal's exploratory drive, consistent with the role of Group II mGluRs in facilitating some types of learning not associated with significantly elevated states of arousal [95]. The potential role of Group III mGluRs in cognition awaits further investigation.…”

Section: Glutamate Regulates Cognitive Function Through Ionotropic Anmentioning

confidence: 91%

Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition

Rahn

Slusher²,

Kaplin³

2012

CMC

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Glutamate, first identified in 1866, is the primary excitatory neurotransmitter in the brain. While it is critically important in many highly regulated cortical functions such as learning and memory, glutamate can be much like the magic the Sorcerer's Apprentice used in Goethe's poem: when conjured under unregulated conditions glutamate can get quickly out of control and lead to deleterious consequences. Two broad types of glutamate receptors, the ionotropic and metabotropic, facilitate glutamatergic neurotransmission in the CNS and play key roles in regulating cognitive function. Excessive activation of these receptors leads to excitotoxicity, especially in brain regions that are developmentally and regionally vulnerable to this kind of injury. Dysregulation of glutamate signaling leads to neurodegeneration that plays a role in a number of neuropsychiatric diseases, prompting the development and utilization of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. Inhibition of the enzyme glutamate carboxypeptidase II (GCPII) is one method of manipulating glutamate neurotransmission. Positive outcomes (decreased neuronal loss, improved cognition) have been demonstrated in preclinical models of ALS, stroke, and Multiple Sclerosis due to inhibition of GCPII, suggesting this method of glutamate regulation could serve as a therapeutic means for treating neurodegeneration and cognitive impairment.

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Section: Glutamate Regulates Cognitive Function Through Ionotropic Anmentioning

confidence: 91%

Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition

Rahn

Slusher²,

Kaplin³

2012

CMC

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“…To ensure that unilateral optogenetic silencing does not cause a generalized sensorimotor or motivational behavioral impairment that could account for the deficit in the left-NpHR group on the spatial long-term memory task, a subset of the same mice, as well as a group of experimentally naïve mice, were trained on an associative, nonspatial visual discrimination T-maze task (16,19) with trial-limited light delivery, as before (10-40 s). Mice had to learn to associate either a gray or a black/white-striped goal arm with reward (Fig.…”

Section: Resultsmentioning

confidence: 99%

Left–right dissociation of hippocampal memory processes in mice

Shipton

El-Gaby

Apergis-Schoute

et al. 2014

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

166

222

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Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory. U nilateral specializations may facilitate greater processing power in bilateral brain structures by using the available neuronal circuitry more effectively. Nevertheless, the nature of the mechanisms that can act within the confines of duplicate neural structures to support different cognitive functions in each hemisphere remains elusive.The hippocampus is essential for certain forms of learning and memory, both in humans (1) and in rodents (2, 3), and also plays an important role in navigation (4). The left and right mammalian hippocampi comprise the same anatomical areas and directional connectivity, and yet in the human hippocampus, taskrelated activity may be localized to only one hemisphere (5). This lateralization may enable the left and right hippocampus to support complementary functions in human episodic memory, with left hippocampal activity associated with an egocentric, sequential representation of space but greater activity in the right hippocampus when an allocentric representation is used (6). It has been suggested that human hippocampal asymmetry is primarily dictated by external asymmetry-namely, the left hemispheric involvement in language processing and the stronger contribution of the right hemisphere to visuosp...

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“…The mGlu2 −/− mice were generated as in [30], mGlu3 −/− mice were generated as in [44] and mGlu2/3 −/− were generated as in [10]. Briefly, mGlu2 −/− mice were crossed with mGlu3 −/− mice to generate double heterozygote offspring.…”

Section: Methodsmentioning

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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Fractionation of Spatial Memory in GRM2/3 (mGlu2/mGlu3) Double Knockout Mice Reveals a Role for Group II Metabotropic Glutamate Receptors at the Interface Between Arousal and Cognition

Cited by 57 publications

References 68 publications

Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition

Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition

Left–right dissociation of hippocampal memory processes in mice

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

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