2. Academic Validation
  3. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex

Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex

  • Cell. 2007 Apr 20;129(2):397-410. doi: 10.1016/j.cell.2007.03.015.
Min Wang 1,  Brian P Ramos,  Constantinos D Paspalas,  Yousheng Shu,  Arthur Simen,  Alvaro Duque,  Susheel Vijayraghavan,  Avis Brennan,  Anne Dudley,  Eric Nou,  James A Mazer,  David A McCormick,  Amy F T Arnsten
Affiliations

Affiliation

  • 1 Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510 USA.
PMID: 17448997 DOI: 10.1016/j.cell.2007.03.015
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.

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