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

Abstract

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...

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

“…Nevertheless, recent studies revealed that theta activity in hippocampus was increased in mGluR7 Ϫ/Ϫ mice and that this alteration of rhythmic activity was associated with the working memory defect (Holscher et al, 2005). It has been demonstrated that increases in the amygdalohippocampal area also coincide with fear conditioning and expression of anxiety and fear-related responses (Seidenbecher et al, 2003).…”

Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

“…Performances in complex working memory tasks such as 8-arm radial maze task were also impaired in mGluR7 knockout mice [133]. Interestingly, the working memory deficit was associated with an increased hippocampal theta power while performing the task, which was suggested to reflect a lack of modulation of local inhibition, in turn leading to decreased neuronal firing threshold and altered spike timing [134]. At the cellular level, mGluR7 knockout mice were reported to exhibit deficits in short-term, but not long-term potentiation in the hippocampus [135], findings in agreement with the hypothesis that short-term potentiation represents the cellular substrate for short-term memory and critical for working memory performances.…”

The NTSR1 gene modulates the association between hippocampal structure and working memory performance

“…For example, electrophysiological studies with rodents have demonstrated that WM performance is correlated with both the magnitude of long-term depression in the hippocampus (Nakao et al, 2002) and the theta rhythm in the hippocampus (Holscher et al, 2005). A rodent pharmacological study showed that WM impairment was accompanied by the deposition of Amyloid beta-peptide (Abeta) in the hippocampus (Leighty et al, 2004).…”