1. Fairless R, Masius H, Rohlmann A, et al. {{Polarized Targeting of Neurexins to Synapses Is Regulated by their C-Terminal Sequences}}. {J Neurosci};2008 (Nov 26);28(48):12969-12981.
Two families of cell-adhesion molecules, predominantly presynaptic neurexins and postsynaptic neuroligins, are important for the formation and functioning of synapses in the brain, and mutations in several genes encoding these transmembrane proteins have been found in autism patients. However, very little is known about how neurexins are targeted to synapses and which mechanisms regulate this process. Using various epitope-tagged neurexins in primary hippocampal neurons of wild-type and knock-out mice in vitro and in transgenic animals in vivo, we show that neurexins are trafficked throughout neurons via transport vesicles and the plasma membrane insertion of neurexins occurs preferentially in the axonal/synaptic compartment. We also observed that exit of neurexins from the ER/Golgi and correct targeting require their PDZ-binding motif at the C terminus, whereas two presumptive ER retention signals are inactive. The ubiquitous presence of neurexin-positive transport vesicles and absence of bassoon colabeling demonstrate that these carriers are not active zone precursor vesicles, but colocalization with CASK, RIM1alpha, and calcium channels suggests that they may carry additional components of the exocytotic machinery. Our data indicate that neurexins are delivered to synapses by a polarized and regulated targeting process that involves PDZ-domain mediated interactions, suggesting a novel pathway for the distribution of neurexins and other synaptic proteins.
2. Krysko KM, Rutherford MD. {{A threat-detection advantage in those with autism spectrum disorders}}. {Brain Cogn};2008 (Nov 24)
Identifying threatening expressions is a significant social perceptual skill. Individuals with autism spectrum disorders (ASD) are impaired in social interaction, show deficits in face and emotion processing, show amygdala abnormalities and display a disadvantage in the perception of social threat. According to the anger superiority hypothesis, angry faces capture attention faster than happy faces in individuals with a history of typical development [Hansen, C. H., & Hansen, R. D. (1988). Finding the face in the crowd: An anger superiority effect. Journal of Personality and Social Psychology, 54(6), 917-924]. We tested threat detection abilities in ASD using a facial visual search paradigm. Participants were asked to detect an angry or happy face image in an array of distracter faces. A threat-detection advantage was apparent in both groups: participants showed faster and more accurate detection of threatening over friendly faces. Participants with ASD showed similar reaction time, but decreased overall accuracy compared to controls. This provides evidence for less robust, but intact or learned implicit processing of basic emotions in ASD.
3. Rehnstrom K, Ylisaukko-Oja T, Nummela I, et al. {{Allelic variants in HTR3C show association with autism}}. {Am J Med Genet B Neuropsychiatr Genet};2008 (Nov 26)
Autism spectrum disorders (ASDs) are severe neurodevelopmental disorders with a strong genetic component. Only a few predisposing genes have been identified so far. We have previously performed a genome-wide linkage screen for ASDs in Finnish families where the most significant linkage peak was identified at 3q25-27. Here, 11 positional and functionally relevant candidate genes at 3q25-27 were tested for association with autistic disorder. Genotypes of 125 single nucleotide polymorphisms (SNPs) were determined in 97 families with at least one individual affected with autistic disorder. The most significant association was observed using two non-synonymous SNPs in HTR3C, rs6766410 and rs6807362, both resulting in P = 0.0012 in family-based association analysis. In addition, the haplotype C-C corresponding to amino acids N163-A405 was overtransmitted to affected individuals (P = 0.006). Sequencing revealed no other variants in the coding region or splice sites of HTR3C. Based on the association analysis results in a previously identified linkage region, we propose that HTR3C represents a novel candidate locus for ASDs and should be tested in other populations. (c) 2008 Wiley-Liss, Inc.
4. Repicky SE, Broadie K. {{Metabotropic Glutamate Receptor Mediated Use-Dependent Down-regulation of Synaptic Excitability Involves the Fragile X Mental Retardation Protein}}. {J Neurophysiol};2008 (Nov 26)
Loss of the mRNA-binding protein FMRP results in the most common inherited form of both mental retardation and autism spectrum disorders: Fragile X Syndrome (FXS). The leading FXS hypothesis proposes that metabotropic glutamate receptor (mGluR) signaling at the synapse controls FMRP function in the regulation of local protein translation to modulate synaptic transmission strength. In this study, we use the Drosophila FXS disease model to test the relationship between Drosophila FMRP (dFMRP) and the sole Drosophila mGluR (dmGluRA) in regulation of synaptic function, utilizing two-electrode voltage-clamp recording at the glutamatergic neuromuscular junction (NMJ). Null dmGluRA mutants display minimal changes in basal synapse properties, but pronounced defects during sustained high frequency stimulation (HFS). The double null dfmr1;dmGluRA mutant shows repression of enhanced augmentation and delayed onset of premature long-term facilitation (LTF), and strongly reduces grossly elevated post-tetanic potentiation (PTP) phenotypes present in dmGluRA null animals. Null dfmr1 mutants display features of synaptic hyperexcitability, including multiple transmission events in response to a single stimulus and cyclic modulation of transmission amplitude during prolonged HFS. The double null dfmr1;dmGluRA mutant shows amelioration of these defects, but does not fully restore wildtype properties in dfmr1 null animals. These data suggest that dmGluRA functions in a negative feedback loop in which excess glutamate released during high frequency transmission binds the glutamate receptor to dampen synaptic excitability, and dFMRP functions to suppress the translation of proteins regulating this synaptic excitability. Removal of the translational regulator partially compensates for loss of the receptor and, similarly, loss of the receptor weakly compensates for loss of the translational regulator.
