1. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex.
- Author
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Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, and Arnsten AF
- Subjects
- Adrenergic alpha-Agonists pharmacology, Animals, Cyclic AMP metabolism, Cyclic Nucleotide-Gated Cation Channels, Dendritic Spines chemistry, Dendritic Spines ultrastructure, Electrophysiology, Guanfacine pharmacology, Ion Channels analysis, Macaca mulatta, Male, Neurons chemistry, Prefrontal Cortex cytology, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, alpha-2 analysis, Ion Channels physiology, Memory, Short-Term physiology, Neurons physiology, Prefrontal Cortex physiology, Receptors, Adrenergic, alpha-2 physiology
- Abstract
Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.
- Published
- 2007
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