Astrocytes, Noradrenaline, α1-Adrenoreceptors, and Neuromodulation: Evidence and Unanswered Questions

Abstract

Noradrenaline is a major neuromodulator in the central nervous system (CNS). It is released from varicosities on neuronal efferents, which originate principally from the main noradrenergic nuclei of the brain - the locus coeruleus - and spread throughout the parenchyma. Noradrenaline is released in response to various stimuli and has complex physiological effects, in large part due to the wide diversity of noradrenergic receptors expressed in the brain, which trigger diverse signaling pathways. In general, however, its main effect on CNS function appears to be to increase arousal state. Although the effects of noradrenaline have been researched extensively, the majority of studies have assumed that noradrenaline exerts its effects by acting directly on neurons. However, neurons are not the only cells in the CNS expressing noradrenaline receptors. Astrocytes are responsive to a range of neuromodulators - including noradrenaline. In fact, noradrenaline evokes robust calcium transients in astrocytes across brain regions, through activation of α1-adrenoreceptors. Crucially, astrocytes ensheath neurons at synapses and are known to modulate synaptic activity. Hence, astrocytes are in a key position to relay, or amplify, the effects of noradrenaline on neurons, most notably by modulating inhibitory transmission. Based on a critical appraisal of the current literature, we use this review to argue that a better understanding of astrocyte-mediated noradrenaline signaling is therefore essential, if we are ever to fully understand CNS function. We discuss the emerging concept of astrocyte heterogeneity and speculate on how this might impact the noradrenergic modulation of neuronal circuits. Finally, we outline possible experimental strategies to clearly delineate the role(s) of astrocytes in noradrenergic signaling, and neuromodulation in general, highlighting the urgent need for more specific and flexible experimental tools.

Keywords: astrocyte calcium; astrocyte–neuron interaction; neuromodulation; noradrenaline (NA); norepinephrine (NE); α1-adrenergic receptors; α1-adrenoceptor.

FIGURE 1

Schematic of astrocyte – neuron interactions and the role of α1-NAR signaling. (A) NA is released from LC varicosities into the extracellular space. (B) Activation of α1-NAR on astrocytes elicits [Ca^{2 +}]_i transients. (C) GABAergic interneurons also express α1-NAR. (D) Astrocytes appear capable of integrating information across signaling modalities: α1-NAR signaling ‘primes’ astrocytes to local glutamatergic synapse activity. (E) Astrocytes also integrate activity at GABAergic synapses, through co-activation of neuropeptide receptors (NPR) and GABA_B receptors. (F) One consequence of astrocyte stimulation is modulation of synaptic activity: one major mechanism by which this occurs is the release of glutamate and D-serine, which activate NMDA receptors, as well as pre-synaptic metabotropic glutamate receptors (mGluR) on neurons. (G) Astrocytes can downregulate GABA_A currents by releasing ATP which acts on neuronal P2X receptors. (H) Astrocytes can transform inhibitory activity at a GABAergic synapse into excitatory signaling at a glutamatergic synapse – a concept known as lateral regulation. (I) The concept of lateral regulation also extends to when functionally coupled astrocytes act as bridges, allowing communication between distant synapses. Mechanisms used are either paracrine secretion (local purinergic signaling), or direct transfer of the [Ca^{2 +}]_i signal (or metabolites) through gap-junctions. (J) Integrating synaptic activity with α1-NAR signaling allows astrocytes to participate in the “Glutamate Amplifies Noradrenergic Effects” (GANE) mechanism, in which astrocytes act in a positive feedback loop releasing glutamate, which acts on receptors located in LC axons to stimulate further noradrenaline release. (K) A mechanism analogous to “GANE” may also act at GABAergic synapses, with astrocytes transforming GABAergic activity into glutamate release. For purposes of clarity, the size of the different elements are not drawn to scale. In the legend key, R, receptor.