Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity, 2012, Lovatt et al.

[jnmaciuch]

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity​

Ditte Lovatt, Qiwu Xu, Wei Liu, Takahiro Takano, Nathan A. Smith, Jurgen Schnermann, Kim Tieu, Maiken Nedergaard

Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca2+ photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity.

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[jnmaciuch]

A more detailed overview from the discussion:

In the present study, we show that active spiking neurons release adenosine through ENTs, leading to suppression of excitatory transmission. We propose that this mechanism functions as a fatigue feedback signal to prevent metabolic exhaustion under high-intensity activity, which otherwise would lead to uncontrolled neuronal signaling. Using acute brain slices, we first showed that only one ectoenzyme, Nt5e, catalyzed extracellular adenosine formation from AMP (Fig. 1). Using this information, we next dissected the role of Nt5e in physiological activation of the A1 receptor in vivo and in acute brain slices. Our analysis showed that neither genetic deletion nor pharmacological inhibition of Nt5e played a role in A1 receptor activation, suggesting that adenosine is not generated in the extracellular space from ATP, but rather is released directly (Figs. 2 and 3). Moreover, uncaging of caged Ca2+ triggered slowly propagating astrocytic Ca2+ wave, but did not inhibit excitatory transmission (Fig. 4). However, when we selectively increased firing of a single excitatory neuron, A1 receptors were activated in an ENT-dependent and Nt5e-independent fashion (Fig. 5), suggesting that active spiking neurons release adenosine. Together, these data demonstrate that, although astrocytic ATP is released simultaneously with seizure activity in vivo and HFS in acute brain slices, ATP is not degraded into adenosine in sufficient quantities to cause A1 receptor-mediated synaptic depression.

 

[jnmaciuch]

Explain like I'm brain foggy:

Adenosine is a molecule with multiple functions in the body--it is one of the 4 nucleotides used to encode DNA and RNA, it is the building block of ATP for cellular metabolism, and it has direct effect as a neurotransmitter.

Caffeine primarily works by blocking adenosine receptors, which inhibits the inhibitory effect of adenosine (and thus produces feelings of wakefulness).

This study shows two main things:
1) Excessive neural firing results in buildup of adenosine, which then inhibits continued neuron firing. The authors propose that this is how neurons regulate themselves to prevent damage from excessive metabolic demand from intense cognitive tasks.
2) The adenosine comes from neurons themselves, not astrocytes (which have a main role of supporting metabolism of neurons).

Failure of adenosine to inhibit continued neural firing is thought to underlie epileptic seizures.