Intellectual disabilities (IDs) and autism spectrum disorders link to human APC inactivating gene mutations. However, little is known about adenomatous polyposis coli’s (APC’s) role in the mammalian brain. This study is the first direct test of the impact of APC loss on central synapses, cognition and behavior. Using our newly generated APC conditional knock-out (cKO) mouse, we show that deletion of this single gene in forebrain neurons leads to a multisyndromic neurodevelopmental disorder. APC cKO mice, compared with wild-type littermates, exhibit learning and memory impairments, and autistic-like behaviors (increased repetitive behaviors, reduced social interest). To begin to elucidate neuronal changes caused by APC loss, we focused on the hippocampus, a key brain region for cognitive function. APC cKO mice display increased synaptic spine density, and altered synaptic function (increased frequency of miniature excitatory synaptic currents, modestly enhanced long-term potentiation). In addition, we found excessive β-catenin levels and associated changes in canonical Wnt target gene expression and N-cadherin synaptic adhesion complexes, including reduced levels of presenilin1. Our findings identify some novel functional and molecular changes not observed previously in other genetic mutant mouse models of co-morbid cognitive and autistic-like disabilities. This work thereby has important implications for potential therapeutic targets and the impact of their modulation. We provide new insights into molecular perturbations and cell types that are relevant to human ID and autism. In addition, our data elucidate a novel role for APC in the mammalian brain as a hub that links to and regulates synaptic adhesion and signal transduction pathways critical for normal cognition and behavior.
The auxiliary subunit ␣ 2 ␦3 modulates the expression and function of voltage-gated calcium channels. Here we show that ␣ 2 ␦3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of ␣ 2 ␦3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. ␣ 2 ␦3 Ϫ/Ϫ mice learned to discriminate pure tones, but they failed to discriminate temporally structured amplitude-modulated tones. Light and electron microscopy analyses revealed reduced levels of presynaptic Ca 2ϩ channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in ␣ 2 ␦3 Ϫ/Ϫ mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the ␣ 2 ␦3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders.
Pirone A, Schredelseker J, Tuluc P, Gravino E, Fortunato G, Flucher BE, Carsana A, Salvatore F, Grabner M. Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cav␣1S-subunit. Am J Physiol Cell Physiol 299: C1345-C1354, 2010. First published September 22, 2010; doi:10.1152/ajpcell.00008.2010.-To identify the genetic locus responsible for malignant hyperthermia susceptibility (MHS) in an Italian family, we performed linkage analysis to recognized MHS loci. All MHS individuals showed cosegregation of informative markers close to the voltage-dependent Ca 2ϩ channel (CaV) ␣1S-subunit gene (CACNA1S) with logarithm of odds (LOD)-score values that matched or approached the maximal possible value for this family. This is particularly interesting, because so far MHS was mapped to Ͼ178 different positions on the ryanodine receptor (RYR1) gene but only to two on CACNA1S. Sequence analysis of CACNA1S revealed a c.4060AϾT transversion resulting in amino acid exchange T1354S in the IVS5-S6 extracellular pore-loop region of CaV␣1S in all MHS subjects of the family but not in 268 control subjects. To investigate the impact of mutation T1354S on the assembly and function of the excitation-contraction coupling apparatus, we expressed GFP-tagged ␣1ST1354S in dysgenic (␣1S-null) myotubes. Whole cell patch-clamp analysis revealed that ␣1ST1354S produced significantly faster activation of L-type Ca 2ϩ currents upon 200-ms depolarizing test pulses compared with wild-type GFP-␣1S (␣1SWT). In addition, ␣1ST1354S-expressing myotubes showed a tendency to increased sensitivity for caffeine-induced Ca 2ϩ release and to larger action-potential-induced intracellular Ca 2ϩ transients under low (Յ2 mM) caffeine concentrations compared with ␣1SWT. Thus our data suggest that an additional influx of Ca 2ϩ due to faster activation of the ␣1ST1354S L-type Ca 2ϩ current, in concert with higher caffeine sensitivity of Ca 2ϩ release, leads to elevated muscle contraction under pharmacological trigger, which might be sufficient to explain the MHS phenotype. Skeletal muscle EC coupling is known as a signaling mechanism (10) between the sarcolemmal voltage-gated L-type Ca 2ϩ channel and the SR Ca 2ϩ release channel or ryanodine receptor type-1 (RyR1). Membrane depolarization induces conformational changes in the voltage sensing and pore forming Ca V ␣ 1S -subunit of the L-type Ca 2ϩ channel, which opens the RyR1 via protein-protein interaction. Consequently, Ca 2ϩ released from the SR stores activates the contractile apparatus of the muscle fibers. Genes encoding the key proteins of the EC coupling machinery are the molecular suspects for MH susceptibility. Linkage studies established the RyR1 gene (RYR1) as the main relevant gene (23, 24) that accounts for MHS in Ͼ50% of MH families. So far, a genome-wide search has identified additional MHS loci on chromosomes 1q32 (26) (MHS5, OMIM 601887) where the gene coding for the Ca V ␣ 1S -subunit is located, 7q21-22 (18) (MHS3, OMIM 154276) the gene lo...
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