Pharmacological activation of mGlu5 receptors with the positive allosteric modulator VU0360172, modulates thalamic GABAergic transmission

Celli, Roberta; Wall, Mark J.; Santolini, Ines; Vergassola, Matteo; Menna, Luisa Di; Mascio, Giada; Cannella, Milena; Luijtelaar, Gilles van; Pittaluga, Anna; Ciruela, Francisco; Bruno, Valeria; Nicoletti, Ferdinando; Ngomba, Richard Teke

doi:10.1016/j.neuropharm.2020.108240

Cited by 10 publications

(14 citation statements)

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“…These effects are hypothesised to represent changes in protein expression or location. A recent study [ 90 ] showed that incubation of thalamic slices in VU030172 (5 μM) for 1 h could change the tonic GABA-A receptor current, an effect that appeared to result from a change in GABA uptake and GAT-1 expression. These effects occurred without changes in GAT-1 mRNA and thus do not represent increased transcription but could result from GAT-1 trafficking or increased translation.…”

Section: Discussionmentioning

confidence: 99%

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

Brown

Grayson

Neill

et al. 2023

Cells

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The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine ‘modulation bias’ in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits.

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Section: Discussionmentioning

confidence: 99%

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

Brown

Grayson

Neill

et al. 2023

Cells

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“…Reductions in the expression and function of mGlu5 receptors have been found in the thalamus and somatosensory cortex of WAG/Rij rats, and pharmacological enhancement of mGlu5 receptors with a selective positive allosteric modulator (PAM) was found to reduce SWD frequency in these rats without the development of tolerance (Ngomba et al, 2011;D'Amore et al, 2013;Celli et al, 2020). Present findings suggest that, in WAG/Rij rats, mGlu5 receptors are dysfunctional also in the hippocampus, and this may underlie some cognitive abnormalities observed in these animals (van Luijtelaar et al, 1989;Karson et al, 2012;Jafarian et al 2015;Malyshev et al, 2012;Leo et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Expression and function of mGlu1 and mGlu5 receptors are reduced in the thalamus of symptomatic WAG/Rij rats, and systemic administration of selective mGlu1 or mGlu5 positive allosteric modulators reduces SWD incidence in these animals (Ngomba et al, 2011;D'Amore et al, 2013;. In particular, pharmacological activation of mGlu5 receptors up-regulates the high affinity GABA transporter, GAT-1, and restrains tonic inhibition in the VBT of WAG/Rij rats (Celli et al, 2020), a mechanism that may protect against absence seizures by reducing hyperpolarization in VBT neurons.…”

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confidence: 99%

Group I metabotropic glutamate receptor-mediated long term depression is disrupted in the hippocampus of WAG/Rij rats modelling absence epilepsy

et al. 2021

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“…855/2020-PR]. Immunoblots were analysed as described before [ 35 , 36 ]. OX1 receptors were detected by using rabbit polyclonal antibody (anti-OX1, AB3092, Chemicon, Millipore Corporation, Billerica, MA, 1:1000) and mouse monoclonal antibody for β-actin (1:50000, Sigma, St. Louis, MO).…”

Section: Reduced Ox1 Receptor Expression In the Thalamus And Somatose...mentioning

confidence: 99%

The Orexin System: A Potential Player in the Pathophysiology of Absence Epilepsy

Celli

Luijtelaar

2022

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Background : Absence epilepsy is characterized by the presence of spike-and-wave discharges (SWDs) at the EEG generated within the cortico-thalamo-cortical circuit. The molecular mechanisms involved in the pathophysiology of absence epilepsy are only partially known. WAG/Rij rats older than 2-3 months develop spontaneous SWDs, and they are sensitive to anti-absence medications. Hence, WAG/Rij rats are extensively used as a model for absence epilepsy with predictive validity. Objective : To examine the possibility that the orexin system, which supports the wake status in experimental animals and humans, plays a role in the pathophysiology of absence seizures. Methods : The perspective grounds its method on recent literature along with measurements of orexin receptor type-1 (OX1) protein levels in the thalamus and somatosensory cortex of WAG/Rij rats and non-epileptic Wistar control rats at two ages (25 days and 6-7 months). OX1 protein levels were measured by immunoblotting. Results : The analysis of the current literature suggests that the orexin system might be involved in the pathophysiology of absence epilepsy and might be targeted by therapeutic intervention. Experimental data are in line with this hypothesis showing that OX1 protein levels were reduced in the thalamus and somatosensory cortex of symptomatic WAG/Rij rats (6-7 months of age) with respect to non-epileptic controls, whereas these differences were not seen in pre-symptomatic, 25 days-old WAG/Rij rats. Conclusions : This might pave the way to future studies on the involvement of the orexinergic system in the pathophysiology of SWDs associated with absence epilepsy and its comorbidities.

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Pharmacological activation of mGlu5 receptors with the positive allosteric modulator VU0360172, modulates thalamic GABAergic transmission

Abstract: Please refer to published version for the most recent bibliographic citation information. If a published version is known of, the repository item page linked to above, will contain details on accessing it.

Cited by 10 publications

References 50 publications

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

Group I metabotropic glutamate receptor-mediated long term depression is disrupted in the hippocampus of WAG/Rij rats modelling absence epilepsy

The Orexin System: A Potential Player in the Pathophysiology of Absence Epilepsy

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