Deletion of G_αq in the telencephalon alters specific neurobehavioral outcomes

Abstract

Gαq-coupled receptors are ubiquitously expressed throughout the brain and body, and it has been shown that these receptors and associated signaling cascades are involved in a number of functional outputs, including motor function and learning and memory. Genetic alterations to Gαq have been implicated in neurodevelopmental disorders such as Sturge-Weber syndrome. Some of these associated disease outcomes have been modeled in laboratory animals, but as Gαq is expressed in all cell types, it is difficult to differentiate the underlying circuitry or causative neuronal population. To begin to address neuronal cell type diversity in Gαq function, we utilized a conditional knockout mouse whereby Gαq was eliminated from telencephalic glutamatergic neurons. Unlike the global Gαq knockout mouse, we found that these conditional knockout mice were not physically different from control mice, nor did they exhibit any gross motor abnormalities. However, similarly to the constitutive knockout animal, Gαq conditional knockout mice demonstrated apparent deficits in spatial working memory. Loss of Gαq from glutamatergic neurons also produced enhanced sensitivity to cocaine-induced locomotion, suggesting that cortical Gαq signaling may limit behavioral responses to psychostimulants. Screening for a variety of markers of forebrain neuronal architecture revealed no obvious differences in the conditional knockouts, suggesting that the loss of Gαq in telencephalic excitatory neurons does not result in major alterations in brain structure or neuronal differentiation. Taken together, our results define specific modulation of spatial working memory and psychostimulant responses through disruptions in Gαq signaling within cerebral cortical glutamatergic neurons.

CNS luteinizing hormone receptor activation rescues ovariectomy-related loss of spatial memory and neuronal plasticity

“…To this end, the LHR is a G-protein coupled receptor that signals through Gs, thus activating extracellular signal-related protein kinase (ERK) or the activating protein kinase A (PKA) (Meng et al, 2007;Menon and Menon, 2012); both are critical cascades in long-term potentiation, memory and structural plasticity (English and Sweatt, 1997;Impey et al, 1998;Bach et al, 1999;Blum et al, 1999;Selcher et al, 1999;Hardingham et al, 2001;Wu et al, 2001;Hebert and Dash, 2002;Goldin and Segal, 2003;Zadran et al, 2009;Briz et al, 2013). LHR activation is also known to signal through Gq, driving GSK3β inhibition and β-catenin activation (Breen et al, 2013;Palm et al, 2014), which is also known to be beneficial for cognition, plasticity and is involved in AD neuroprotection (Kleppisch et al, 2001;Kwok et al, 2008;He and Shen, 2009;McQuail et al, 2013;Graham et al, 2015). Lastly, the LHR is internalized in the presence of high levels of its ligand (Hu et al, 1990;Segaloff et al, 1990;Peegel et al, 1994;Min et al, 1998;Kishi et al, 2001), suggesting dysfunction associated with LHR activation (Berry et al, 2008;Ziegler and Thornton, 2010;Burnham et al, 2017) could be mediated through downregulation of LHR levels rather than activation.…”

Targeting primary and metastatic uveal melanoma with a G protein inhibitor

“…Critical issues and questions remain to be addressed, however. YM/FR may exert deleterious as well as therapeutically beneficial effects, because they do not discriminate between wild-type and oncogenic Gq/11 ( 14 ), and target Gq/11-dependent physiological systems ( 21 , 22 , 23 , 24 ) essential for homeostasis and viability ( 25 , 26 , 27 , 28 ). Indeed, YM/FR administered systemically at levels that reduce Gq/11 activity in host systems greater than 50% is likely to be lethal, as suggested by gene dosage studies of Gq/11 knockout mice ( 29 ).…”

A novel Alex3/Gαqprotein complex regulating mitochondrial dynamics, dendritic complexity, and neuronal survival

“…The G q protein subfamily, highly expressed in the nervous system, is localized to the outer mitochondria membrane 19,23 . This subfamily mediates the signaling of important metabotropic receptors (e.g., type I glutamatergic and cholinergic muscarinic receptors) and is involved in a number of physiological processes including motor functions, learning, and memory [24][25][26] . In the mitochondria, G q proteins regulate mitochondrial preprint (which was not certified by peer review) is the author/funder.…”

“…Besides, large duplications affecting ARMCX3 are associated to schizophrenia and autistic disorders (ClinVar, nsv932069) 52 , whereas ARMCX3 variants are associated to metabolic diseases 53 and ARMCX3 is the most prominent gene linked to sleepdisordered breathing hypoxia 54 (Supplementary Table 1). GNAQ (G q ) mutations lead to motor and cognitive dysfunctions [24][25][26] , and cause seizures and mental retardation 55 , whereas mutations and variants in the functionally related genes TRAK2 and RHOT1/2 (Miro1/2) are associated to autism disorders and late-onset neurodegenerative diseases (Supplementary Table S1). Interestingly, Miro1 protein decreases mitophagy via Parkin 38,56 .…”