Hippocampal Gαq/11 but not Gαo-coupled receptors are altered in aging

Abstract

Normal aging may limit the signaling efficacy of certain GPCRs by disturbing the function of specific Gα-subunits and leading to deficient modulation of intracellular functions that subserve synaptic plasticity, learning and memory. Evidence suggests that Gαq/11 is more sensitive to the effects of aging relative to other Gα-subunits, including Gαo. To test this hypothesis, the functionality of Gαq/11 and Gαo were compared in the hippocampus of young (6 months) and aged (24 months) F344×BNF1 hybrid rats assessed for spatial learning ability. Basal GTPγS-binding to Gαq/11 was significantly elevated in aged rats relative to young and but not reliably associated with spatial learning. mAChR stimulation of Gαq/11 with oxotremorine-M produced equivocal GTPγS-binding between age groups although values tended to be lower in the aged hippocampus and were inversely related to basal activity. Downstream Gαq/11 function was measured in hippocampal subregion CA1 by determining changes in [Ca2+]i after mAChR and mGluR (DHPG) stimulation. mAChR-stimulated peak change in [Ca2+]i was lower in aged CA1 relative to young while mGluR-mediated integrated [Ca2+]i responses tended to be larger in aged. GPCR modulation of [Ca2+]i was observed to depend on intracellular stores to a greater degree in aged than young. In contrast, measures of Gαo-mediated GTPγS-binding were stable across age, including basal, mAChR-, GABABR (baclofen)-stimulated levels. Overall, the data indicate that aging selectively modulates the activity of Gαq/11 within the hippocampus leading to deficient modulation of [Ca2+]i following stimulation of mAChRs but these changes are not related to spatial learning.

Spatial reference memory in normal aging Fischer 344 × Brown Norway F1 hybrid rats

“…All procedures were approved by the Institutional Animal Care and Use Committee of Wake Forest University. Data from a subset of these animals has been reported previously (McQuail et al, 2011, 2013). …”

Molecular aspects of age-related cognitive decline: the role of GABA signaling

“…In addition to GABA A Rs, expression of the GABA B R1 subunit is also reduced throughout the hippocampus of memory-impaired aged rats. Notably, however, lower expression of GABA B R1 is only accompanied by a reduction in GABA B R coupling to its effector G protein in CA3, suggesting that age-related GABA B R signaling dysfunction may be particularly pronounced in this hippocampal subregion [11,13]. Functional consequences for these age-related alterations in GABARs findings are illustrated by in vivo electrophysiological studies in which CA3 pyramidal neuron activity was monitored in behaving young and aged rats.…”

Deletion of Gαq in the telencephalon alters specific neurobehavioral outcomes

“…The hippocampus is important in spatial memory tasks (Burgess et al, ; Martin and Clark, ) and is involved in the neurocircuitry of spontaneous alternation, the key output of the Y‐maze (Lalonde, ). However, others noted that within the hippocampus, aging—not G αq/11 signaling—was detrimental to spatial memory (Mcquail et al, ); this study did not specifically implicate a particular subset of G αq ‐coupled receptors. Regardless, these data indicate that the G αq pathway is important for spatial working memory.…”