title: CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice.
abstract: CALHM1 is a cell surface calcium channel expressed in cerebral neurons. CALHM1 function in the brain remains unknown, but recent results showed that neuronal CALHM1 controls intracellular calcium signaling and cell excitability, two mechanisms required for synaptic function. Here, we describe the generation of Calhm1 knockout (Calhm1(-/-)) mice and investigate CALHM1 role in neuronal and cognitive functions. Structural analysis revealed that Calhm1(-/-) brains had normal regional and cellular architecture, and showed no evidence of neuronal or synaptic loss, indicating that CALHM1 deficiency does not affect brain development or brain integrity in adulthood. However, Calhm1(-/-) mice showed a severe impairment in memory flexibility, assessed in the Morris water maze, and a significant disruption of long-term potentiation without alteration of long-term depression, measured in ex vivo hippocampal slices. Importantly, in primary neurons and hippocampal slices, CALHM1 activation facilitated the phosphorylation of NMDA and AMPA receptors by protein kinase A. Furthermore, neuronal CALHM1 activation potentiated the effect of glutamate on the expression of c-Fos and C/EBPβ, two immediate-early gene markers of neuronal activity. Thus, CALHM1 controls synaptic activity in cerebral neurons and is required for the flexible processing of memory in mice. These results shed light on CALHM1 physiology in the mammalian brain.
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.affiliation: Laboratory of Immune &Neural Networks, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Chang
authors.affiliation: Laboratory of Immune &Neural Networks, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Frattini
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Haitian
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chandakkar
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Adrien
authors.affiliation: Laboratory of Immune &Neural Networks, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Strohl
authors.affiliation: Laboratory of Immune &Neural Networks, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Gibson
authors.affiliation: Monell Chemical Senses Center, Philadelphia, PA 19104, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohmoto
authors.affiliation: Monell Chemical Senses Center, Philadelphia, PA 19104, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Immune &Neural Networks, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.|Department of Molecular Medicine, Hofstra Northwell School of Medicine, Manhasset, NY 11030, USA.
authors.forename: Patricio T
authors.initials: PT
authors.lastname: Huerta
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D015220:Calcium Channels / Q000172:deficiency / Q000378:metabolism*; D003071:Cognition; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D008568:Memory; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: C575356:CALHM1 protein, mouse; D015220:Calcium Channels; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017868:Cyclic AMP-Dependent Protein Kinases