The role of active zone protein Rab3 interacting molecule 1 alpha in the regulation of norepinephrine release, response to novelty, and sleep

Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
Neuroscience (Impact Factor: 3.36). 07/2008; 154(2):821-31. DOI: 10.1016/j.neuroscience.2008.03.047
Source: PubMed


Sleep mechanisms and synaptic plasticity are thought to interact to regulate homeostasis and memory formation. However, the influences of molecules that mediate synaptic plasticity on sleep are not well understood. In this study we demonstrate that mice lacking Rab3 interacting molecule 1 alpha (RIM1 alpha) (Rim1 alpha KO), a protein of the synaptic active zone required for certain types of synaptic plasticity and learning, had 53+/-5% less baseline rapid eye movement (REM) sleep compared with their wild type littermates. Also, compared with wild type littermates, exposure of the mice to an open field or to a novel object induced more robust and longer lasting locomotion suggesting altered habituation. This difference in exploratory behavior correlated with genotype specific changes in REM and deregulated release of norepinephrine in the cortex and basal amygdala of the Rim1 alpha KO mice. Also, moderate sleep deprivation (4 h), a test of the homeostatic sleep response, induced REM sleep rebound with different time course in Rim1 alpha KO and their wild type littermates. As norepinephrine plays an important role in regulating arousal and REM sleep, our data suggest that noradrenergic deficiency in Rim1 alpha KO animals impacts exploratory behavior and sleep regulation and contributes to impairments in learning.

8 Reads
  • Source

    Neuroscience 10/2008; 156(4):1136-1137. DOI:10.1016/j.neuroscience.2008.07.076 · 3.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been known for a long time that genetic factors affect sleep quantity and quality. Genetic screens have identified several mutations that affect sleep across species, pointing to an evolutionary conserved regulation of sleep. Moreover, it has also been recognized that sleep affects gene expression. These findings have given valuable insights into the molecular underpinnings of sleep regulation and function that might lead the way to more efficient treatments for sleep disorders.
    Nature Reviews Neuroscience 09/2009; 10(8):549-60. DOI:10.1038/nrn2683 · 31.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulation of presynaptic voltage-gated calcium channels is critical for depolarization-evoked neurotransmitter release. Various studies attempted to determine the functional implication of Rim1, a component of the vesicle release machinery. Besides to couple voltage-gated Ca(2+) channels to the presynaptic vesicle release machinery, it was evidenced that Rim1 also prevents voltage-dependent inactivation of the channels through a direct interaction with the ancillary β-subunits, thus facilitating neurotransmitter release. However, facilitation of synaptic activity may also be caused by a reduction of the inhibitory pathway carried by G-protein-coupled receptors. Here, we explored the functional implication of Rim1 in G-protein regulation of Ca(v)2.2 channels. Activation of μ-opioid receptors expressed in HEK-293 cells along with Ca(v)2.2 channels produced a drastic current inhibition both in control and Rim1-expressing cells. In contrast, Rim1 considerably promoted the extent of current deinhibition following channel activation, favoring sustained Ca(2+) influx under prolonged activity. Our data suggest that Rim1-induced facilitation of neurotransmitter release may come as a consequence of a decrease in the inhibitory pathway carried by G-proteins that contributes, together with the slowing of channel inactivation, to maintain Ca(2+) influx under prolonged activity. The present study also furthers functional insights in the importance of proteins from the presynaptic vesicle complex in the regulation of voltage-gated Ca(2+) channels by G-proteins.
    Pflügers Archiv - European Journal of Physiology 02/2011; 461(4):447-59. DOI:10.1007/s00424-011-0926-5 · 4.10 Impact Factor
Show more