Abstract
There is growing recognition of the important role of interaction between neurons and glial cells for brain longevity. The extracellular ATP have been shown to bring significant contribution into bi-directional glia-neuron communications, in particular into astrocyte-driven modulation of synaptic plasticity. To elucidate a putative impact of brain aging on neuron-glia networks, we explored the aging-related plasticity of the purinoreceptors-mediated signaling in cortical neurons and astrocytes. We investigated the age- and experience-related alterations in purinergic components of neuronal synaptic currents and astroglial calcium signaling in the layer2/3 of neocortex of mice exposed to the mild caloric restriction (CR) and environmental enrichment (EE) which included ad libitum physical exercise. We observed the considerable age-related decline in the neuronal P2X receptor-mediated miniature spontaneous currents which originated from the release of ATP from both synapses and astrocytes. We also found out that purinergic astrocytic Ca2+-signaling underwent the substantial age-related decline but EE and CR rescued astroglial signaling, in particular mediated by P2X1, P2X1/5, and P2Y1 receptors. Our data showed that age-related attenuation in the astroglial calcium signaling caused a substantial decrease in the exocytosis of ATP leading to impairment of astroglia-derived purinergic modulation of excitatory synaptic currents and GABAergic tonic inhibitory currents. On a contrary, exposure to EE and CR, which enhanced purinergic astrocytic calcium signaling, up-regulated the excitatory and down-regulated the inhibitory currents in neurons of old mice, thus counterbalancing the impact of aging on synaptic signaling. Combined, our results strongly support the physiological importance of ATP-mediated signaling for glia-neuron interactions and brain function. Our data also show that P2 purinoreceptor-mediated communication between astrocytes and neurons in the neocortex undergoes remodeling during brain aging and decrease in the ATP release may contribute to the age-related impairment of synaptic transmission.
Highlights
Adaptation of mammalian brain to environmental and biochemical challenges across a life-time is associated with remodeling of synaptic contacts and plastic changes in the neural networks (Hillman et al, 2008; Nithianantharajah and Hannan, 2009; van Praag, 2009; Mercken et al, 2012; Merzenich et al, 2014)
We compared animals kept under standard housing conditions (SH) vs animals exposed to the enriched environment (EE) from birth (Correa et al, 2012), including ad libitum access to the running wheel, or kept on mild caloric restriction (CR) diet for 4–6 weeks
Mice were kept under SH or exposed either to enriched environment (EE) or CR; the details are given in Methods
Summary
Adaptation of mammalian brain to environmental and biochemical challenges across a life-time is associated with remodeling of synaptic contacts and plastic changes in the neural networks (Hillman et al, 2008; Nithianantharajah and Hannan, 2009; van Praag, 2009; Mercken et al, 2012; Merzenich et al, 2014). Release of ATP from astrocytes represents a powerful pathway of glia-neuron interaction implicated in the synaptic plasticity (Araque et al, 2014; Rasooli-Nejad et al, 2014; Pankratov and Lalo, 2015; Lalo et al, 2016), meta-plasticity (Hulme et al, 2014; Lalo et al, 2018), and neurological disorders (Butt, 2011; Rodrigues et al, 2015; Rivera et al, 2016; Verkhratsky et al, 2017). Apart from mediating a significant component of glia-to-neuron signaling, astrocyte-derived ATP can act in autocrine manner activating purinoreceptor-mediated Ca2+signaling in astroglial networks (Fields and Stevens, 2000; Fields and Burnstock, 2006; Gourine et al, 2010; Butt, 2011; Lalo et al, 2011b; Wells et al, 2015)
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