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Review
. 2012 Nov;37(11):2496-512.
doi: 10.1007/s11064-012-0818-x. Epub 2012 Jun 21.

Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance

John O'Donnell  1 , Douglas Zeppenfeld, Evan McConnell, Salvador Pena, Maiken Nedergaard
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Review

Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance

John O'Donnell et al. Neurochem Res. .
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Abstract

Norepinephrine (NE) is a neuromodulator that in multiple ways regulates the activity of neuronal and non-neuronal cells. NE participates in the rapid modulation of cortical circuits and cellular energy metabolism, and on a slower time scale in neuroplasticity and inflammation. Of the multiple sources of NE in the brain, the locus coeruleus (LC) plays a major role in noradrenergic signaling. Processes from the LC primarily release NE over widespread brain regions via non-junctional varicosities. We here review the actions of NE in astrocytes, microglial cells, and neurons based on the idea that the overarching effect of signaling from the LC is to maximize brain power, which is accomplished via an orchestrated cellular response involving most, if not all cell types in CNS.

Figures

Fig. 1
Noradrenergic receptor expression on cortical astrocytes and their downstream effects. α1-Adrenergic receptor stimulation leads to increased glutamate uptake from the extracellular space by increasing activity of the sodium-dependent glutamate transporters (GLT1/GLAST). α2-Adrenergic receptor stimulation leads to increased glycogenesis. β1-Adrenergic receptor stimulation causes increased clearance of K+ by increased activity of the Na+/K+-ATPase pump and drives glycogenolysis
Fig. 2
Noradrenergic stimulation of Microglia. 1 NE regulates microglia disease response by enhancing phagocytosis and soma migration while suppressing proliferation and cytokine production. 2 NE enhances cell survival via activation of two parallel pathways: induction of astrocytic BDNF production and suppression of microglial cytokine production. 3 NE may constitutively suppresses synaptic scaling up by suppressing TNFα production and inducing BDNF production
Fig. 3
Noradrenergic stimulation of neurons. 1 β-Adrenergic receptor activation leads to decreased spike frequency adaptation by inhibiting SK channels in a cAMP-PKA dependent pathway. 2 PKA activation from β-adrenergic receptor activation increases membrane GluR1 insertion. 3 β-Adrenergic receptor activation sensitizes excitatory neurons to inhibitory inputs by increasing GABAAR currents. 4 α2-Adrenergic receptor activation closes the non-selective cation, cAMP gated, HCN channel to increase neuronal network firing. 5 The βγ subunit (Giβγ) of the G-protein coupled to the α2-adrenergic receptor blocks the Cav2.2 channel decreasing neurotransmitter release. 6 α1-Adrengergic receptors may inhibit the action of the α2-adrenergic receptor’s coupled Giβγ subunit’s Cav2.2 activity through PKC mediated phosphorylation of Giβγ’s binding site. Activation of α1 receptors decrease resting potassium conductance, directly depolarizing interneurons. Note: α2 receptors are found predominately on dendritic and axonal processes, causing localized effects
Fig. 4
Progression of memory consolidation in chicks. Memory consolidation in the intermediate medial mesopallium of the newly hatched chicken (corresponding to the mammalian cerebral cortex) progresses through several phases in the hour following learning. The transition between these are marked by critical periods (black wedges) at approximately 7.5, 30, and 60 min post-learning, where astrocytic glycogenolysis, driven by the serotonergic receptor, 5-HT2B, in the first period and by the β2-adrenergic receptor in the next two periods, is necessary for memories to be retained. NE-mediated β2-adrenergic receptor activity is accompanied by α2-adrenergic receptor driven glycogenesis, which is necessary for the recovery and maintenance of glycogen levels. Inhibitors of glycogenolysis (DAB) and adrenergic receptors are listed under the periods where their administration prevents memory formation
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