title: The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses.
abstract: Glutamate release from photoreceptor terminals is controlled by voltage-dependent calcium channels (VDCCs). In humans, mutations in the Cacna1f gene, encoding the alpha1F subunit of VDCCs, underlie the incomplete form of X-linked congenital stationary night blindness (CSNB2). These mutations impair synaptic transmission from rod and cone photoreceptors to bipolar cells. Here, we report anatomical and functional characterizations of the retina in the nob2 (no b-wave 2) mouse, a naturally occurring mutant caused by a null mutation in Cacna1f. Not surprisingly, the b-waves of both the light- and dark-adapted electroretinogram are abnormal in nob2 mice. The outer plexiform layer (OPL) is disorganized, with extension of ectopic neurites through the outer nuclear layer that originate from rod bipolar and horizontal cells, but not from hyperpolarizing bipolar cells. These ectopic neurites continue to express mGluR6, which is frequently associated with profiles that label with the presynaptic marker Ribeye, indicating potential points of ectopic synapse formation. However, the morphology of the presynaptic Ribeye-positive profiles is abnormal. While cone pedicles are present their morphology also appears compromised. Characterizations of visual responses in retinal ganglion cells in vivo, under photopic conditions, demonstrate that ON-center cells have a reduced dynamic range, although their basic center-surround organization is retained; no alteration in the responses of OFF-center cells was evident. These results indicate that nob2 mice are a valuable model in which to explore the pathophysiological mechanisms associated with Cacna1f mutations causing CSNB2, and the subsequent effects on visual information processing. Further, the nob2 mouse represents a model system in which to define the signals that guide synapse formation and/or maintenance in the OPL.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Philippa R
authors.initials: PR
authors.lastname: Bayley
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Brecha
authors.forename: Muriel T
authors.initials: MT
authors.lastname: Davisson
authors.forename: Norm L
authors.initials: NL
authors.lastname: Hawes
authors.forename: Arlene A
authors.initials: AA
authors.lastname: Hirano
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Hurd
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ikeda
authors.forename: Britt A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McCall
authors.forename: Catherine W
authors.initials: CW
authors.lastname: Morgans
authors.forename: Steve
authors.initials: S
authors.lastname: Nusinowitz
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Rice
authors.forename: Kirstan A
authors.initials: KA
authors.lastname: Vessey
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gregg
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000367:Age Factors; D000429:Alcohol Oxidoreductases; D000818:Animals; D064026:Calbindins; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D003623:Dark Adaptation / Q000502:physiology; D004307:Dose-Response Relationship, Radiation; D004596:Electroretinography / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D019887:Peanut Agglutinin; D010750:Phosphoproteins / Q000378:metabolism; D010775:Photic Stimulation / Q000379:methods; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014795:Visual Pathways / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: C480684:Cacna1f protein, mouse; D064026:Calbindins; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D019887:Peanut Agglutinin; D010750:Phosphoproteins; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D018042:Receptors, Neurokinin-3; D064030:S100 Calcium Binding Protein G; C113897:metabotropic glutamate receptor 6; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; D011493:Protein Kinase C