Cortistatin-expressing interneurons require TrkB signaling to suppress neural hyper-excitability

Abstract

Signaling of brain-derived neurotrophic factor (BDNF) via tropomyosin receptor kinase B (TrkB) plays a critical role in the maturation of cortical inhibition and controls expression of inhibitory interneuron markers, including the neuropeptide cortistatin (CST). CST is expressed exclusively in a subset of cortical and hippocampal GABAergic interneurons, where it has anticonvulsant effects and controls sleep slow-wave activity (SWA). We hypothesized that CST-expressing interneurons play a critical role in regulating excitatory/inhibitory balance, and that BDNF, signaling through TrkB receptors on CST-expressing interneurons, is required for this function. Ablation of CST-expressing cells caused generalized seizures and premature death during early postnatal development, demonstrating a critical role for these cells in providing inhibition. Mice in which TrkB was selectively deleted from CST-expressing interneurons were hyperactive, slept less and developed spontaneous seizures. Frequencies of spontaneous excitatory post-synaptic currents (sEPSCs) on CST-expressing interneurons were attenuated in these mice. These data suggest that BDNF, signaling through TrkB receptors on CST-expressing cells, promotes excitatory drive onto these cells. Loss of excitatory drive onto CST-expressing cells that lack TrkB receptors may contribute to observed hyperexcitability and epileptogenesis.

TrkB Signaling Influences Gene Expression in Cortistatin-Expressing Interneurons

“…Specifically, mice in which TrkB is depleted in Cort interneurons develop spontaneous seizures and die ϳ1 month after birth. Before developing seizures, these mice sleep for significantly less time and display hyperlocomotion (Hill et al, 2019). While this study established that TrkB signaling in Cort interneurons is critical to maintain appropriate levels of cortical excitability, the molecular mechanisms mediating Cort interneuron dysfunction downstream of TrkB signaling remain known.…”

“…We selectively depleted TrkB in Cort-expressing cells by crossing mice in which Cre-recombinase is expressed under control of the endogenous Cort promoter (Cort tm1(cre)Zjh /J; referenced in text as Cort Cre ; stock# 010910, The Jackson Laboratory; RRID:IMSR_JAX: 010910; Taniguchi et al, 2011) to mice carrying a loxPflanked TrkB allele (strain fB/fB, referenced in text as TrkB flox/flox (Grishanin et al, 2008;Baydyuk et al, 2011;Hill et al, 2019). Cort Cre mice were received from The Jackson Laboratory on a mixed C57BL/6J ϫ 129S background.…”

“…While BDNF is expressed primarily in excitatory pyramidal neurons, but not in inhibitory interneurons, its receptor TrkB is widely expressed in both excitatory and inhibitory neurons (Cellerino et al, 1996;Gorba and Wahle, 1999;Swanwick et al, 2004). Levels of TrkB expression across different interneuron classes have not been explicitly quantified, but we previously reported that ϳ50% of Cort-expressing interneurons express TrkB in the cortex (Hill et al, 2019).…”

Thermoregulatory Fear of Harm Mood Disorder: In Depth Exploration of a Unique Juvenile-Onset Phenotype That Provides a Parsimonious Clinical Description of Certain Youths with Highly Comorbid Treatment Refractory Psychiatric Disorders

“…First, translational studies show that the homeostatic increase in sleep pressure for restorative SWS that builds during wakefulness is further moderated by the amount of exploratory behavior and cortical activation that occurs during this time, and that this is mediated by the degree of cortical BDNF expression [52][53][54]. More specifically it appears that activity-dependent BDNF expression increases sleep pressure by acting through tropomyosin receptor kinase B (TrkB) receptors on a subset of cortical and hippocampal GABAergic interneurons that express the neuropeptide cortistatin, which plays a critical role in regulating cortical inhibitory balance and degree of SWS activity [55,56]. Mice in which TrkB was selectively deleted from cortistatinexpressing interneurons sleep less and due to insufficient cortical inhibition become hyperactive and develop spontaneous seizures [56].…”

“…More specifically it appears that activity-dependent BDNF expression increases sleep pressure by acting through tropomyosin receptor kinase B (TrkB) receptors on a subset of cortical and hippocampal GABAergic interneurons that express the neuropeptide cortistatin, which plays a critical role in regulating cortical inhibitory balance and degree of SWS activity [55,56]. Mice in which TrkB was selectively deleted from cortistatinexpressing interneurons sleep less and due to insufficient cortical inhibition become hyperactive and develop spontaneous seizures [56].…”