Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes

Abstract

Activity-dependent brain-derived neurotrophic factor (BDNF) signaling through receptor tyrosine kinase B (TrkB) is required for cued fear memory consolidation and extinction. Although BDNF is primarily secreted from glutamatergic neurons, TrkB is expressed by other genetically defined cells whose contributions to the behavioral effects of BDNF remain poorly understood. Parvalbumin (PV)-positive interneurons, which are highly enriched in TrkB, are emerging as key regulators of fear memory expression. We therefore hypothesized that activity-dependent BDNF signaling in PV-interneurons may modulate emotional learning. To test this hypothesis, we utilized the LoxP/Cre system for conditional deletion of TrkB in PV-positive cells to examine the impact of cell-autonomous BDNF signaling on Pavlovian fear conditioning and extinction. However, behavioral abnormalities indicative of vestibular dysfunction precluded the use of homozygous conditional knockouts in tests of higher cognitive functioning. While vestibular dysfunction was apparent in both sexes, female conditional knockouts exhibited an exacerbated phenotype, including extreme motor hyperactivity and circling behavior, compared to their male littermates. Heterozygous conditional knockouts were spared of vestibular dysfunction. While fear memory consolidation was unaffected in heterozygotes of both sexes, males exhibited impaired extinction consolidation compared to their littermate controls. Our findings complement evidence from human and rodent studies suggesting that BDNF signaling promotes consolidation of extinction and point to PV-positive neurons as a discrete population that mediates these effects in a sex-specific manner.

Multimodal and Site-Specific Plasticity of Amygdala Parvalbumin Interneurons after Fear Learning

“…However, such plasticity may also be a precipitating factor for escalating fear and anxiety in PTSD. Indeed, preclinical animal models suggest that PV-IN dysfunction may be involved in pathological, extinction-resistant fear (Bissonette et al, 2014; Brown et al, 2015; Lucas et al, 2014). Therefore, experiments should examine whether chronic stress or trauma is associated with altered inhibitory plasticity and whether these effects may underlie progression to emotional dysfunction.…”

Sex differences in brain‐derived neurotrophic factor signaling: Functions and implications

“…In fact, in published studies that included both sexes as subjects, more often than not sex‐specific changes have been observed in BDNF expression associated with treatments or manipulations (Advani et al, ; Reverte et al, ; Hill et al, ; Y.C. Wu et al, ; Lucas et al, ; R. Wu et al, ; Gallego et al, ; Nishinaka et al, ; Venezia et al, ). It is therefore safe to say that, when discussing BDNF signaling, sex should be a factor that is always included.…”

Activity-dependent signaling: influence on plasticity in circuits controlling fear-related behavior

“…As demonstrated in a number of genetic models, proper E/I balance is critical in regulating fear and anxiety [35,38,61]. While BDNF is primarily expressed in glutamatergic cells, tropomysin receptor kinase B (TrkB), BDNF's cognate receptor, is expressed in both excitatory and inhibitory neurons [62,63].…”

“…This possibility is strengthened by evidence that TrkB deletion in PV-interneurons decreases their action potential generation [68]. Evidence that heterozygous TrkB deletion in PV-interneurons causes fear extinction deficits suggests that TrkB signaling may contribute to the ability of PV-interneurons to regulate fear [61]. Thus, BDNF's ability to properly regulate fear learning and extinction may be mediated at least in part by its critical role in inhibitory plasticity and E/I balance.…”