Abstract
Aberrant fear is a cornerstone of several psychiatric disorders. Consequently, there is large interest in elucidation of signaling mechanisms that link extracellular cues to changes in neuronal function and structure in brain pathways that are important in the generation and maintenance of fear memory and its behavioral expression. Members of the Plexin-B family of receptors for class 4 semaphorins play important roles in developmental plasticity of neurons, and their expression persists in some areas of the adult nervous system. Here, we aimed to elucidate the role of Semaphorin 4C (Sema4C) and its cognate receptor, Plexin-B2, in the expression of contextual and cued fear memory, setting a mechanistic focus on structural plasticity and exploration of contributing signaling pathways. We observed that Plexin-B2 and Sema4C are expressed in forebrain areas related to fear memory, such as the anterior cingulate cortex, amygdala and the hippocampus, and their expression is regulated by aversive stimuli that induce fear memory. By generating forebrain-specific Plexin-B2 knockout mice and analyzing fear-related behaviors, we demonstrate that Sema4C-PlexinB2 signaling plays a crucial functional role in the recent and remote recall of fear memory. Detailed neuronal morphological analyses revealed that Sema4C-PlexinB2 signaling largely mediates fear-induced structural plasticity by enhancing dendritic ramifications and modulating synaptic density in the adult hippocampus. Analyses on signaling-related mutant mice showed that these functions are mediated by PlexinB2-dependent RhoA activation. These results deliver important insights into the mechanistic understanding of maladaptive plasticity in fear circuits and have implications for novel therapeutic strategies against fear-related disorders.
Highlights
Deregulated fear responses comprise a frequently occurring feature of several debilitating fear-related disorders, including post-traumatic stress disorder, and are characterized by an impaired ability to distinguish between danger and safety-related cues [1, 2]
We commenced this study by analyzing the expression of the gene encoding Plexin-B2, namely plxnb2, over brain areas involved in fear memory and studying potential changes in paradigms of fear memory recall
We observed expression of β-galactosidase in area CA1, area CA3 and the dentate gyrus (DG) of the hippocampus (Fig. 1a) and in other regions involved in fear memory, such as the rostral anterior cingulate cortex (Fig. 1b) and the amygdaloid nuclei (Fig. 1c)
Summary
Deregulated fear responses comprise a frequently occurring feature of several debilitating fear-related disorders, including post-traumatic stress disorder, and are characterized by an impaired ability to distinguish between danger and safety-related cues [1, 2]. It has been postulated that maladaptive plasticity in fear circuits can lead to persistent emotional responses in the lack of imminent danger, and form the basis of debilitating emotional disorders [3]. Understanding circuits and cellular and molecular mechanisms underlying behavioral abnormalities in fear responses is of prime importance towards developing effective therapies. Rodent models of fear learning and memory employ the paradigms of fear conditioning to either an auditory-cued or a context to study memory formation and recall. Freezing responses recorded in rodents to auditory or contextual cues
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
