Rett syndrome (RTT) is a neurodevelopmental disorder affecting multiple functions, including the norepinephrine (NE) system. In the CNS, NE is produced mostly by neurons in the locus coeruleus (LC), where defects in intrinsic neuronal properties, NE biosynthetic enzymes, neuronal CO2 sensitivity, and synaptic currents have been reported in mouse models of RTT. LC neurons in methyl-CpG-binding protein 2 gene (Mecp2) null mice show a high rate of spontaneous firing, although whether such hyperexcitability might increase or decrease the NE release from synapses is unknown. To activate the NEergic axonal terminals selectively, we generated an optogenetic mouse model of RTT in which NEergic neuronal excitability can be manipulated with light. Using commercially available mouse breeders, we produced a new strain of double-transgenic mice with Mecp2 knockout and channelrhodopsin (ChR) knockin in catecholaminergic neurons. Several RTT-like phenotypes were found in the tyrosine hydroxylase (TH)-ChR-Mecp2(-/Y) mice, including hypoactivity, low body weight, hindlimb clasping, and breathing disorders. In brain slices, optostimulation produced depolarization and an increase in the firing rate of LC neurons from TH-ChR control mice. In TH-ChR control mice, optostimulation of presynaptic NEergic neurons augmented the firing rate of hypoglossal neurons (HNs), which was blocked by the α-adrenoceptor antagonist phentolamine. Such optostimulation of NEergic terminals had almost no effect on HNs from two or three TH-ChR-Mecp2(-/Y) mice, indicating that excessive excitation of presynaptic neurons does not benefit NEergic modulation in mice with Mecp2 disruption. These results also demonstrate the feasibility of generating double-transgenic mice for studies of RTT with commercially available mice, which are inexpensive, labor/time efficient, and promising for cell-specific stimulation. © 2016 Wiley Periodicals, Inc.
Pubmed ID: 27317352 RIS Download
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View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets Green Fluorescent Protein (GFP)
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View all literature mentionsThis unknown targets Biotin
View all literature mentionsThis unknown targets Rabbit IgG, whole molecule
View all literature mentionsThis polyclonal targets human, mouse, rat
View all literature mentionsThis unknown targets Rabbit IgG, whole molecule
View all literature mentionsThis polyclonal targets human, mouse, rat
View all literature mentionsMus musculus with name B6.129P2(C)-Mecp2tm1.1Bird/J from IMSR.
View all literature mentionsMus musculus with name B6;129S-Gt(ROSA)26Sortm32(CAG-COP4*H134R/EYFP)Hze/J from IMSR.
View all literature mentionsMus musculus with name B6.129P2(C)-Mecp2tm1.1Bird/J from IMSR.
View all literature mentionsMus musculus with name B6.Cg-7630403G23RikTg(Th-cre)1Tmd/J from IMSR.
View all literature mentionsMus musculus with name B6;129S-Gt(ROSA)26Sortm32(CAG-COP4*H134R/EYFP)Hze/J from IMSR.
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