Astrocytes may function as mediators of the impact of noradrenaline on neuronal function. Activation of glial α1-adrenergic receptors triggers rapid astrocytic Ca 2+ elevation and facilitates synaptic plasticity, while activation of β-adrenergic receptors elevates cAMP levels and modulates memory consolidation. However, the dynamics of these processes in behaving mice remain unexplored, as do the interactions between the distinct second messenger pathways. Here we simultaneously monitored astrocytic Ca 2+ and cAMP and demonstrate that astrocytic second messengers are regulated in a temporally distinct manner. In behaving mice, we found that while an abrupt facial air puff triggered transient increases in noradrenaline release and large cytosolic astrocytic Ca 2+ elevations, cAMP changes were not detectable. By contrast, repeated aversive stimuli that lead to prolonged periods of vigilance were accompanied by robust noradrenergic axonal activity and gradual sustained cAMP increases. Our findings suggest distinct astrocytic signaling pathways can integrate noradrenergic activity during vigilance states to mediate distinct functions supporting memory.

Ipsilateral and contralateral hippocampal CA3-CA1 and CA2-CA1 projections were investigated in adult male Long-Evans rats by retrograde tracing. Injection of the retrograde tracer cholera toxin subunit B in the strata oriens and radiatum of dorsal CA1 resulted in labeling of predominantly pyramidal cells in ipsilateral and contralateral CA3 and CA2. The contralateral and ipsilateral anterior-posterior extents of CA3 innervation to CA1 were similar. Fifteen to twenty per cent of the hippocampus proper cells that give rise to CA1 stratum oriens innervation were CA2 pyramidal cells, whereas CA2 cells were a mere 3% for CA1 stratum radiatum innervation. The preferred projection of CA2 pyramidal cells to the CA1 stratum oriens was also manifested in transgenic mice that express GFP under the control of the CACNG5 promoter, in which CA2 cells express high amounts of GFP. The ratios of ipsilateral to contralateral projections were compared. For the CA3-CA1 connection, we found that dorsal CA1 stratum radiatum received more ipsilateral projections whereas CA1 stratum oriens received more contralateral innervation. Interestingly, ipsilateral connections dominated for both CA2-CA1 stratum oriens and CA2-CA1 stratum radiatum. These results demonstrate that the primary intrahippocampal target of CA2 pyramidal cells is the ipsilateral CA1 stratum oriens, in contrast to CA3 cells which project more diversely to bilateral CA1 regions. Such innervation patterns may suggest differential dendritic information processing in apical and basal dendrites of CA1 pyramidal cells.

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Spontaneous waves of cortical spreading depolarization (CSD) are induced in the setting of acute focal ischemia. CSD is linked to a sharp increase of extracellular K + that induces a long-lasting suppression of neural activity. Furthermore, CSD induces secondary irreversible damage in the ischemic brain, suggesting that K + homeostasis might constitute a therapeutic strategy in ischemic stroke. Here we report that adrenergic receptor (AdR) antagonism accelerates normalization of extracellular K + , resulting in faster recovery of neural activity after photothrombotic stroke. Remarkably, systemic adrenergic blockade before or after stroke facilitated functional motor recovery and reduced infarct volume, paralleling the preservation of the water channel aquaporin-4 in astrocytes. Our observations suggest that AdR blockers promote cerebrospinal fluid exchange and rapid extracellular K + clearance, representing a potent potential intervention for acute stroke.photothrombotic stroke | adrenergic receptor | extracellular potassium ion | aquaporin-4 | AQP4T he ionic composition of the intracellular and extracellular environments in the central nervous system critically influences neuronal networks since action potentials and synaptic input rely on transmembrane electrochemical gradients. Acute stroke disrupts the ion homeostasis in the involving infarct and induces repeated spontaneous waves of cortical spreading depolarization (CSD) in patients (1, 2) and in experimental stroke models (3-5). CSD is initiated as a slowly propagating wave of depolarization that travels across the cortical surface with a velocity of ∼4 mm/min (6). Increases in extracellular potassium (K + ) and glutamate are mediators of CSD (7-10). During the peak of CSD, the extracellular potassium concentration [K + ] e rises from a basal level of 3.5-4.5 to 30-60 mM. This massive rise of [K + ] e depolarizes neurons and astrocytes, resulting in the release of neurotransmitters and the opening of voltage-dependent K + channels and N-methyl-D-aspartate receptors (NMDARs, K + -permeable glutamate receptors), which in a positive feedforward trigger an autoregenerative elevation of [K + ] e as CSD propagates across the cortex (11). The membrane depolarization inactivates voltage-dependent Na + channels, resulting in prolonged electrical silence of neurons. Neurons will gradually regain responsiveness during the recovery period concurrently with normalization of ionic gradients including that of [K + ] e . However, the factors determining [K + ] e recovery are poorly understood, in part because there have been few attempts to monitor cortex-wide network activity linked to CSD following stroke incidents.Astrocytes, a major glial cell type, play a key role in the uptake of K + and the maintenance of ionic homeostasis through Na + -K + pumps (12) and K + channels (13). Additionally, K + uptake is regulated by astrocytic Ca 2+ signaling (14). In experimental animal models, the focal application of high K + on the cortical surface reliably evokes CSD (7). While ...

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