α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex
| Autor: | Constantinos D. Paspalas, Arthur A. Simen, Susheel Vijayraghavan, Avis R. Brennan, Alvaro Duque, Eric Nou, David A. McCormick, Amy F.T. Arnsten, Yousheng Shu, James A. Mazer, Anne G Dudley, Min Wang, Brian P. Ramos |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Dendritic spine Dendritic Spines Cyclic Nucleotide-Gated Cation Channels Prefrontal Cortex Stimulation Biology Spatial memory MOLNEURO General Biochemistry Genetics and Molecular Biology Ion Channels Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Postsynaptic potential Receptors Adrenergic alpha-2 HCN channel Cyclic AMP Animals Prefrontal cortex 030304 developmental biology Neurons 0303 health sciences Working memory Biochemistry Genetics and Molecular Biology(all) Macaca mulatta Guanfacine Rats Electrophysiology Memory Short-Term Pyrimidines nervous system biology.protein Neuroscience Adrenergic alpha-Agonists 030217 neurology & neurosurgery |
| Zdroj: | Cell. 129(2):397-410 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2007.03.015 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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