Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory

Hölscher, Christian; Schmid, Susanne; Pilz, P.; Sansig, Gilles; Putten, Herman van der; Plappert, Claudia F.

doi:10.1016/j.bbr.2004.03.015

Cited by 88 publications

(61 citation statements)

References 44 publications

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“…The results of this study confirm the finding of our previous work (Hölscher et al 2004), which demonstrated that mice lacking mGluR7 show selective performance deficits in tasks assessing WM, but no deficits in reference memory tasks. The EEG recordings during rest showed a high Delta band activity as expected in animals that are either inactive or in non-REM sleep (Vanderwolf 1969).…”

Section: Discussionsupporting

confidence: 91%

“…In a previous study it was found that the number of line crossings in the open field per time unit was not significantly different (Hölscher et al 2004). This showed that the KO animals were not overtly different in their excitability or basic motor activity compared with the wild-type group.…”

Section: Speed Analysismentioning

confidence: 83%

“…We wondered whether Theta rhythm in these mice might be affected. These findings, together with the selective defects in WM observed in mGluR7 KO mice in the earlier study (Hölscher et al 2004), prompted us to record hippocampal EEGs in mGluR7 KO during rest and during the performance of a complex WM task. Our hypothesis was that if Theta oscillations do play a role in supporting and storing WM, Theta rhythm should be affected in the mGluR7 KO mice.…”

mentioning

confidence: 88%

“…After day one, visits to arms that were never baited were considered reference memory errors, which is a type of long-term memory error in this design since the animals had 9 d to learn which arms were baited. Each animal had two runs per day for 9 d (see also Hölscher et al [2004] and Jarrard [1983] for more details on this task).…”

Section: Taskmentioning

confidence: 99%

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Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory

Hölscher

Schmid²,

Pilz³

et al. 2005

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Metabotropic glutamate receptors (mGluRs) are known to play a role in synaptic plasticity and learning. We have previously shown that mGluR7 deletion in mice produces a selective working memory (WM) impairment, while other types of memory such as reference memory remain unaffected. Since WM has been associated with Theta activity (6-12 Hz) in EEGs, and since EEG abnormalities have been observed in these mice before, we studied the effect of mGluR7 gene ablation on EEG activity in the hippocampus, in particular in the Theta range, during performance of a WM task. In an eight-arm maze with four arms baited, mGluR7 knock-out (KO) and wild-type mice committed the same number of reference memory errors, whereas KOs committed more WM errors. While performing the task, KO mice showed substantially higher Theta amplitudes, and the ratio of Theta to overall EEG power was much increased. No change was seen in the Delta (0-5 Hz), or Gamma (30-40 Hz) EEG bands compared with controls. When recording EEGs during periods of rest in the home cages, no difference was seen between groups. These findings suggest that mGluR7 is important for modulation and control of Theta activity. Since only WM was affected, and only the Theta range of EEG activity was altered, these results show a correlation between Theta rhythm and WM performance, and therefore support the concept that Theta activity in the hippocampus is involved in WM storage.Metabotropic glutamate receptors (mGluRs) are a family of glutamate-sensitive receptors that are coupled to intracellular signal transduction via G-proteins (Pin and Duvoisin 1995). It is known that mGluRs play an important role in the regulation of CNS synaptic plasticity, and also in some processes of memory formation. Pharmacological blockade of mGluR group III receptors (subtypes 4, 6, 7, and 8) has profound effects on the induction of synaptic plasticity (Bashir et al. 1993;Richter-Levin et al. 1994;Hölscher et al. 1997a), synaptic depression (Manahan-Vaughan 2000;Weber et al. 2002), and spatial learning (Hölscher et al. 1996(Hölscher et al. , 1999.In a previous study, we tested the effect of mGluR7 deletion on different forms of learning and memory formation (Hölscher 2003). We showed that mGluR7-deficient (knock-out; KO) mice were not impaired in a non-associative habituation task or in performing reference memory tasks of different complexities (open field, T-maze, four-and eight-arm mazes). However, in tasks that require increased capacity of working memory (WM) performance, mGluR7 KO mice showed clear deficits.WM contains task-related information required to develop plans of action and to guide behavior (Baddeley and Hitch 1974;Olton et al. 1979). In the present paper, we adhere to the definition of WM by Olton et al. (1979), who emphasized the importance of hippocampal activity for supporting WM. How WM is actually encoded and stored in the brain has been under investigation for a long time. The occurrence of oscillations in the EEG of subjects that performed WM tasks had been observed. In pa...

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Section: Discussionsupporting

confidence: 91%

Section: Speed Analysismentioning

confidence: 83%

mentioning

confidence: 88%

Section: Taskmentioning

confidence: 99%

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Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory

Hölscher

Schmid²,

Pilz³

et al. 2005

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“…Behavioral studies in mGluR7-deficient mice indicate an involvement of mGluR7 in specific aspects of anxiety and emotional responding (Cryan et al, 2003;Mitsukawa et al, 2005). Additionally, Holscher et al (2004) described deficits in spatial working memory in these mice, suggesting that the model could be suitable to investigate the association between higher-level cognitive processes, anxiety, and fear conditioning.…”

Section: Introductionmentioning

confidence: 93%

Concomitant Deficits in Working Memory and Fear Extinction Are Functionally Dissociated from Reduced Anxiety in Metabotropic Glutamate Receptor 7-Deficient Mice

Callaerts-Végh

Beckers

Ball

et al. 2006

Journal of Neuroscience

149

124

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Metabotropic glutamate receptor 7 (mGluR7), a receptor with a distinct brain distribution and a putative role in anxiety, emotional responding, and spatial working memory, could be an interesting therapeutic target for fear and anxiety disorders. mGluR7-deficient (mGluR7 Ϫ/Ϫ ) mice showed essentially normal performance in tests for neuromotor and exploratory activity and passive avoidance learning but prominent anxiolytic behavior in two anxiety tests. They showed a delayed learning curve during the acquisition of the hidden-platform water maze, and three interspersed probe trials indicated that mGluR7 Ϫ/Ϫ mice were slower to acquire spatial information. Working memory in the water maze task and the radial arm maze was impaired in mGluR7 Ϫ/Ϫ mice compared with mGluR7 ϩ/ϩ . mGluR7 Ϫ/Ϫ mice also displayed a higher resistance to extinction of fear-elicited response suppression in a conditioned emotional response protocol. In a non-fear-based water maze protocol, mGluR7 Ϫ/Ϫ mice displayed similar delayed extinction. These observed behavioral changes are probably not attributable to changes in AMPA or NMDA receptor function because expression levels of AMPA and NMDA receptors were unaltered. Extinction of conditioned fear is an active and context-dependent form of inhibitory learning and an experimental model for therapeutic fear reduction. It appears to depend on glutamatergic and higher-level brain functions similar to those involved in spatial working memory but functionally dissociated from those that mediate constitutional responses in anxiety tests.

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Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Marafi

Mitani

Işıkay³

et al. 2020

Ann Clin Transl Neurol

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Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-proteincoupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T: p.Arg659Ter). Developmental delay, neonatal-or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late 610 childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

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Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory

Cited by 88 publications

References 44 publications

Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory

Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory

Concomitant Deficits in Working Memory and Fear Extinction Are Functionally Dissociated from Reduced Anxiety in Metabotropic Glutamate Receptor 7-Deficient Mice

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

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