title: Pannexin1 stabilizes synaptic plasticity and is needed for learning.
abstract: Pannexin 1 (Panx1) represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and K(ATP) channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1(-/-) mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR)-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4) accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1(-/-) mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.
authors.affiliation: Neuroanatomy, Medical Faculty, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Prochnow
authors.forename: Amr
authors.initials: A
authors.lastname: Abdulazim
authors.forename: Stefan
authors.initials: S
authors.lastname: Kurtenbach
authors.forename: Verena
authors.initials: V
authors.lastname: Wildförster
authors.forename: Galina
authors.initials: G
authors.lastname: Dvoriantchikova
authors.forename: Julian
authors.initials: J
authors.lastname: Hanske
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petrasch-Parwez
authors.forename: Valery I
authors.initials: VI
authors.lastname: Shestopalov
authors.forename: Rolf
authors.initials: R
authors.lastname: Dermietzel
authors.forename: Denise
authors.initials: D
authors.lastname: Manahan-Vaughan
authors.forename: Georg
authors.initials: G
authors.lastname: Zoidl
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001007:Anxiety; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D017630:Connexins / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D013216:Reflex, Startle / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D000255:Adenosine Triphosphate