Purines released from astrocytes inhibit excitatory synaptic transmission in the ventral horn of the spinal cord

Abstract

Spinal neuronal networks are essential for motor function. They are involved in the integration of sensory inputs and the generation of rhythmic motor outputs. They continuously adapt their activity to the internal state of the organism and to the environment. This plasticity can be provided by different neuromodulators. These substances are usually thought of being released by dedicated neurons. However, in other networks from the central nervous system synaptic transmission is also modulated by transmitters released from astrocytes. The star-shaped glial cell responds to neurotransmitters by releasing gliotransmitters, which in turn modulate synaptic transmission. Here we investigated if astrocytes present in the ventral horn of the spinal cord modulate synaptic transmission. We evoked synaptic inputs in ventral horn neurons recorded in a slice preparation from the spinal cord of neonatal mice. Neurons responded to electrical stimulation by monosynaptic EPSCs (excitatory monosynaptic postsynaptic currents). We used mice expressing the enhanced green fluorescent protein under the promoter of the glial fibrillary acidic protein to identify astrocytes. Chelating calcium with BAPTA in a single neighboring astrocyte increased the amplitude of synaptic currents. In contrast, when we selectively stimulated astrocytes by activating PAR-1 receptors with the peptide TFLLR, the amplitude of EPSCs evoked by a paired stimulation protocol was reduced. The paired-pulse ratio was increased, suggesting an inhibition occurring at the presynaptic side of synapses. In the presence of blockers for extracellular ectonucleotidases, TFLLR did not induce presynaptic inhibition. Puffing adenosine reproduced the effect of TFLLR and blocking adenosine A1 receptors with 8-Cyclopentyl-1,3-dipropylxanthine prevented it. Altogether our results show that ventral horn astrocytes are responsible for a tonic and a phasic inhibition of excitatory synaptic transmission by releasing ATP, which gets converted into adenosine that binds to inhibitory presynaptic A1 receptors.

Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS

“…In amyotrophic lateral sclerosis (ALS), the "excitotoxic model" hypothesized that pathological increase in glutamatergic input at synaptic level and/or neuronal hyperexcitability would cause Ca 2+ overload and disruption of mitochondria and ultimately lead to motoneuron (MN) death (Rothstein, 2009). In spinal muscular atrophy (SMA), a distinct MN disease, the reduced efficacy of the presynaptic terminals of Ia afferents (which originate from muscle spindles and provide direct, powerful excitation to MNs; Binder et al, 1993) disrupts MN firing (Mentis et al, 2011) and causes MN hyperexcitability (Fletcher et al, 2017). Likewise, in a Drosophila model of SMA, loss of the Smn gene in interneurons projecting to MNs is sufficient to cause MN degeneration (Imlach et al, 2012), confirming that disruption of synaptic inputs can drive MN vulnerability.…”

Activating mu-opioid receptors in the spinal cord mediates the cardioprotective effect of remote preconditioning of trauma

“…Activation of adenosine receptors in the spinal cord suppressed neutrophil adhesion in peripheral inflammatory locations via adenosine upregulation [9,22]. Several studies have confrmed the effects of adenosine on nervous tissue, including inhibition of the release of several classes of neurotransmitters, such as glutamate, through adenosine receptor activation [23,24]. In the presence of inflammation, the hyperexcitability of neurons increased, and glutamate conferred this effect [25,26].…”

3D in vitro modeling of the central nervous system

“…Astrocytes (or astroglia) are also the greatest in number and perform a myriad of functions including BBB homeostasis (Hawkins and Davis, 2005), volume regulation (Iacovetta et al, 2012), neuronal metabolism assistance through lactate shuttling (Schurr et al, 1997), neurotransmitter and ion buffering (Wong et al, 2013), disease (Schlachetzki et al, 2013; Sturrock, 1976), and secretion of basal lamina (Liesi et al, 1983). Astrocytes have also been shown to engage in slow-wave calcium signaling, and are hypothesized to contribute to the electrical behavior of neurons (Carlsen and Perrier, 2014). The other glial cell types are less diverse in subtype, however tend to be less well-understood.…”