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The Journal of Neuroscience, February 20, 2008, 28(8):1804-1815; doi:10.1523/JNEUROSCI.4616-07.2008

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Cellular/Molecular
Noradrenergic Modulation of Electrical Coupling in GABAergic Networks of the Hippocampus

Veronika Zsiros and Gianmaria Maccaferri

Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Correspondence should be addressed to Gianmaria Maccaferri, Department of Physiology, Northwestern University Medical School, 303 East Chicago Avenue, Tarry Building, Room 5-707 M211, Chicago, IL 60611. Email: g-maccaferri{at}northwestern.edu

Noradrenergic modulation of cortical circuits is involved in information processing, regulation of higher functions, and prevention of epileptic activity. Here, we studied the effects of noradrenaline on the functional connectivity of GABAergic networks of the hippocampus and show that electrical synapses between interneurons are a novel target of noradrenergic modulation in vitro. Application of noradrenaline or of the selective β-adrenergic agonist isoproterenol decreased gap junction-based coupling in paired recordings from stratum lacunosum-moleculare interneurons by 40%. Similar results were obtained after pharmacological stimulation of the adenylyl cyclase with forskolin. In contrast, the adenylyl cyclase antagonist MDL12330A [cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine] or the specific protein kinase A (PKA) inhibitor H89 (N-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride) enhanced the basal strength of coupling by 30%. In addition, PKA-mediated phosphorylation was critical for both isoproterenol- and forskolin-dependent regulation of coupling, because inclusion of the PKA antagonist KT5720 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylicacid hexyl ester] in the recording pipettes prevented modulation.

Lastly, we studied the effects of β-adrenergic modulation on mixed polysynaptic transmission within the GABAergic network. Isoproterenol depressed propagation of GABA_A receptor-mediated synaptic currents, but did not change significantly direct GABAergic input, indicating that regulation of electrical coupling adds flexibility to the information flow generated by chemical synapses.

In conclusion, activation of β-adrenergic receptors in stratum lacunosum-moleculare GABAergic networks reduces electrical synaptic transmission via a cAMP/PKA signaling cascade, and affects the degree of synaptic divergence within the circuit. We propose that this dynamic modulation and interplay between electrical and chemical synaptic transmission in GABAergic networks contributes to the tuning of memory processes in vivo, and prevents hypersynchronous activity.

Key words: noradrenaline; GABAergic neuron; gap junction; cAMP; adenylate cyclase; network

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Received Oct. 10, 2007; revised Jan. 7, 2008; accepted Jan. 8, 2008.

Correspondence should be addressed to Gianmaria Maccaferri, Department of Physiology, Northwestern University Medical School, 303 East Chicago Avenue, Tarry Building, Room 5-707 M211, Chicago, IL 60611. Email: g-maccaferri{at}northwestern.edu

This article has been cited by other articles:

				P. R. L. Parker, S. J. Cruikshank, and B. W. Connors Stability of Electrical Coupling despite Massive Developmental Changes of Intrinsic Neuronal Physiology J. Neurosci., August 5, 2009; 29(31): 9761 - 9770. [Abstract] [Full Text] [PDF]

				P. B. Schwarz, N. Yee, S. Mir, and J. H. Peever Noradrenaline triggers muscle tone by amplifying glutamate-driven excitation of somatic motoneurones in anaesthetized rats J. Physiol., December 1, 2008; 586(23): 5787 - 5802. [Abstract] [Full Text] [PDF]

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