The role of active zone protein Rab3 interacting molecule 1 alpha in the regulation of norepinephrine release, response to novelty, and sleep.
ABSTRACT 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.
Article: Mammalian sleep genetics.[Show abstract] [Hide abstract]
ABSTRACT: Mammalian sleep is a complex phenomenon governed by the interplay of neural circuits and signaling systems. The impact of genetic manipulations on sleep-wake dynamics provides important insights into this complex behavior. Here we review the sleep-related phenotypes of over 50 transgenic animal models spanning a variety of signaling systems. This heterogeneous literature includes outcomes spanning motor activity patterns, sleep-wake stage architecture, responses to sleep deprivation, circadian rhythmicity, and other perturbations such as food restriction, temperature challenge, and infection exposure. Insights from these animal experiments hold potential to converge with the well-known sleep-wake neurocircuitry as well as the increasingly available human genetic information, especially in patient populations exhibiting sleep-wake pathology.Neurogenetics 09/2012; 13(4):287-326. · 2.66 Impact Factor
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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. · 4.87 Impact Factor
- Neuroscience 10/2008; 156(4):1136-1137. · 3.33 Impact Factor