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An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons
Author(s) -
Zhang Shuang,
Johnson Christopher M.,
Cui Ningren,
Xing Hao,
Zhong Weiwei,
Wu Yang,
Jiang Chun
Publication year - 2016
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23760
Subject(s) - mecp2 , optogenetics , rett syndrome , neuroscience , locus coeruleus , photostimulation , genetically modified mouse , biology , catecholaminergic cell groups , transgene , tyrosine hydroxylase , excitatory postsynaptic potential , chemistry , endocrinology , medicine , inhibitory postsynaptic potential , central nervous system , phenotype , dopamine , biochemistry , gene
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 CO 2 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.