In-vivo genetic ablation of metabotropic glutamate receptor type 5 slows down disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Blocking glutamate mGlu5 receptors with the negative allosteric modulator CTEP improves disease course in SOD1G93A mouse model of amyotrophic lateral sclerosis

“…These receptors are actively involved in many pathophysiological cellular processes, such as maintenance of glutamate homeostasis and synaptic plasticity (Panatier & Robitaille, 2016 ; Vermeiren et al, 2005 ), glial activation (Aronica et al, 2000 ; D'Antoni et al, 2008 ), mitochondria dysfunction and oxidative stress (Li et al, 2011 ), intracellular calcium levels and downstream signalling cascades (Liu et al, 2014 ), neuroinflammation (Drouin‐Ouellet et al, 2011 ) and the pro‐inflammatory NF‐κB pathway (Shah et al, 2012 ), and immune system stimulation (Liu et al, 2014 ; Pacheco et al, 2004 ). Moreover, recent in vivo work from our group showed that constitutive genetic ablation of mGlu 5 receptors in the SOD1 G93A mouse significantly increased survival probability and slowed the progression of the pathology (Bonifacino et al, 2017 ; Bonifacino, Provenzano, et al, 2019 ). Also there are several reports of mGlu5 receptors affecting a variety of cellular processes in ALS (Anneser et al, 1999 ; Brownell et al, 2015 ; Rossi et al, 2008 ; Vergouts et al, 2018 ; Vermeiren et al, 2006 ).…”

“…How comparable effects on cellular disease markers and similar CTEP distribution in SOD1 G93A mice could reflect different impacts of CTEP on the disease progression in males and females is difficult to explain. This issue becomes even more complex because we have already seen sex‐selective responses after in vivo genetic ablation of mGlu 5 receptors in SOD1 G93A mice, with the effects more pronounced in male mice (Bonifacino et al, 2017 ; Bonifacino, Provenzano, et al, 2019 ). Of note, sex‐specific male‐oriented effects have been described also in a CTEP‐treated mouse model of Alzheimer's disease (Abd‐Elrahman et al, 2019 ).…”

“…We found that the mGlu 1 and mGlu 5 receptors sited at glutamatergic spinal cord nerve terminals of SOD1 G93A mice are abnormally sensitive to the mGlu 1/5 receptor agonist ( S )‐3,5‐dihydroxyphenylglycine ( 3,5‐DHPG ), with the mGlu5 receptors being the most involved in this hypersensitivity (Bonifacino, Rebosio, et al, 2019 ; Giribaldi et al, 2013 ). Further, we demonstrated that reducing the expression of mGlu 1 or mGlu 5 receptors in SOD1 G93A mice, overall, ameliorates disease progression (Bonifacino et al, 2017 ; Bonifacino, Provenzano, et al, 2019 ; Milanese et al, 2014 ). Specifically, the genetic ablation of mGlu 5 receptors produced delayed pathology onset and survival improvement, ameliorated motor skills, enhanced number of preserved MNs, decreased astrocyte and microglia activation, reduced cytosolic free Ca 2+ and normalized the excessive glutamate release in the spinal cord of SOD1 G93A mice (Bonifacino et al, 2017 ; Bonifacino, Provenzano, et al, 2019 ).…”

“…Further, we demonstrated that reducing the expression of mGlu 1 or mGlu 5 receptors in SOD1 G93A mice, overall, ameliorates disease progression (Bonifacino et al, 2017 ; Bonifacino, Provenzano, et al, 2019 ; Milanese et al, 2014 ). Specifically, the genetic ablation of mGlu 5 receptors produced delayed pathology onset and survival improvement, ameliorated motor skills, enhanced number of preserved MNs, decreased astrocyte and microglia activation, reduced cytosolic free Ca 2+ and normalized the excessive glutamate release in the spinal cord of SOD1 G93A mice (Bonifacino et al, 2017 ; Bonifacino, Provenzano, et al, 2019 ).…”

Enhanced Function and Overexpression of Metabotropic Glutamate Receptors 1 and 5 in the Spinal Cord of the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis during Disease Progression

“…The abnormal activity of mGluR1 and mGluR5 demonstrated previously [26] and in the present work further support the rationale for the therapeutic exploitation of reducing mGluR1/5 activity. Indeed, we demonstrated that the genetic reduction [64,65] or ablation [66] of mGluR1 or mGluR5 in SOD1 G93A mice positively affects the disease course in SOD1 G93A mice, prolonging survival, ameliorating motor skills, and improving biochemical and cellular parameters that are altered during the progression of ALS. These in vivo data are supported by previous in vitro evidence indicating positive effects of group I mGluR activity inhibition on MNs degeneration [67,68,69].…”