RT Journal Article
SR Electronic
T1 TrkB signaling influences gene expression in cortistatin-expressing interneurons
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0310-19.2019
DO 10.1523/ENEURO.0310-19.2019
A1 Kristen R. Maynard
A1 Alisha Kardian
A1 Julia L. Hill
A1 Yishan Mai
A1 Brianna Barry
A1 Henry L. Hallock
A1 Andrew E. Jaffe
A1 Keri Martinowich
YR 2020
UL http://www.eneuro.org/content/early/2020/01/13/ENEURO.0310-19.2019.abstract
AB Brain-derived neurotrophic factor (BDNF) signals through its cognate receptor tropomyosin kinase B (TrkB) to promote the function of several classes of inhibitory interneurons. We previously reported that loss of BDNF-TrkB signaling in cortistatin-expressing (Cort) interneurons leads to behavioral hyperactivity and spontaneous seizures in mice. We performed bulk RNA sequencing (RNA-seq) from the cortex of mice with disruption of BDNF-TrkB signaling in cortistatin interneurons, and identified differential expression of genes important for excitatory neuron function. Using translating ribosome affinity purification (TRAP) and RNA-seq, we define a molecular profile for Cort-expressing inhibitory neurons and subsequently compared the translatome of normal and TrkB-depleted Cort neurons, revealing alterations in calcium signaling and axon development. Several of the genes enriched in Cort neurons and differentially expressed in TrkB depleted neurons are also implicated in autism and epilepsy. Our findings highlight TrkB-dependent molecular pathways as critical for the maturation of inhibitory interneurons and support the hypothesis that loss of BDNF signaling in Cort interneurons leads to altered excitatory/inhibitory balance.SIGNIFICANCE STATEMENT Mounting evidence suggests that brain-derived neurotrophic factor (BDNF) signals through its receptor TrkB to promote inhibitory interneuron function, including a sub-population of cortistatin-expressing (Cort) neurons. This study identifies how TrkB depletion in Cort neurons impacts the Cort interneuron transcriptome as well as gene expression in the surrounding cellular milieu of mouse cortex. Our findings highlight TrkB-dependent molecular pathways in the maturation of inhibitory interneurons and further implicate BDNF signaling as critical for regulating excitatory/inhibitory balance. We identified BDNF-regulation of a number of genes expressed in Cort neurons that are implicated in both autism and epilepsy, which is of note because these conditions are highly comorbid, and are hypothesized to share underlying molecular mechanisms.