An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.
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.
Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302.
Shuang
S
Zhang
Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302.
Christopher M
CM
Johnson
Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302.
Ningren
N
Cui
Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302.
Hao
H
Xing
Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302.
Weiwei
W
Zhong
Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302.
Yang
Y
Wu
Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302.
Chun
C
Jiang
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D005260:Female; D008125:Locus Coeruleus / Q000473:pathology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism*; D062308:Optogenetics; D010646:Phentolamine / Q000494:pharmacology; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D008164:Luminescent Proteins; D051783:Methyl-CpG-Binding Protein 2; D012243:Rhodopsin; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine; D010646:Phentolamine
AB_10049285; AB_10055152; AB_2337237; AB_2566814; AB_258613; IMR_JAX:008601; IMSR_JAX:003890; IMSR_JAX:012569; Mecp2; NE modulation; Rett syndrome; SCR_011323; double transgenic; optogenetics