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Ablation of PHOX2B‐Derived Astrocytes Results in Neuronal Dystrophy‐Like Neuropathology in the RTN
Author(s) -
Melo e Silva Talita,
Czeisler Catherine M,
Fair Summer R,
AlzateCorrea Diego,
Takakura Ana C T,
Moreira Thiago S,
Otero Jose J
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.546.4
Subject(s) - biology , cre recombinase , astrocyte , microbiology and biotechnology , axon , neuroscience , anatomy , central nervous system , transgene , genetically modified mouse , genetics , gene
The transcription factor Phox2b is a regulator of the autonomic nervous system development and is especially expressed by respiratory circuits involved in chemosensory integration, as neurons of solitary tract nucleus (NTS) that relay information from peripheral chemoreceptors to the ventral respiratory column, and by central chemoreceptors located in the retrotrapezoid nucleus (RTN). In addition to neurons, recent studies show that astrocytes from ventral medullary surface also detect PCO 2 increase, and contribute to respiratory drive. Since PHOX2B biased progenitor cells generate astrocytes that have a developmental connection with RTN neurons, the aim of this study is determine the extent to which selective ablation of these astrocytes affect synapse integrity in the retrotrapezoid nucleus. We utilized the astrocyte ablation technique described by Tsai et al., 2012. In this model, the astrocyte‐specific ALDH1L1 promoter induces GFP expression in the absence of cre recombinase, and in the presence of cre recombinase expresses diphtheria toxin A (DTA). We interbred ALDH1L1 loxp‐GFP‐STOP‐loxp‐DTA mice to PHOX2B cre mice. Transmission electron photomicrographs were captured from the RTN/VLM area and morphometric analysis was performed using FIJI. We noted that axon terminals in the mutants ( PHOX2B cre , ALDH1L1 loxp‐GFP‐STOP‐loxp‐DTA ) were on average larger in area and perimeter. Furthermore, we noted an increase in the percentage of axon terminals showing autophagic vacuoles/phagosomes. The proportion of axon terminals with other organelles, including mitochondria and dense core neurosecretory vesicles, was not different between groups. In summary, PHOX2B‐derived, astrocyte ablated mice show synaptic pathology characterized by dysmorphic neuroaxonal morphology, suggesting an underlying defect in the afferent input into the RTN. These data suggest that PHOX2B‐derived astrocytes may play a role in regulating the synaptic integrity of neuronal inputs into RTN neurons. Other experiments are being performed in order to elucidate if the cell body of these neurons is located in the commissural NTS, and also, if PHOX2b derived astrocytes depletion can imply local regulation of presynaptic autophagy, which can lead to neurodegeneration and breathing impair. Support or Funding Information FAPESP and NIH This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .