Amygdala regulation of fear and emotionality in fragile X syndrome

Abstract

Fear is a universal response to a threat to one's body or social status. Disruption in the detection and response of the brain's fear system is commonly observed in a variety of neurodevelopmental disorders, including fragile X syndrome (FXS), a brain disorder characterized by variable cognitive impairment and behavioral disturbances such as social avoidance and anxiety. The amygdala is highly involved in mediating fear processing, and increasing evidence supports the idea that inhibitory circuits play a key role in regulating the flow of information associated with fear conditioning in the amygdala. Here, we review the known and potential importance of amygdala fear circuits in FXS, and how developmental studies are critical to understand the formation and function of neuronal circuits that modulate amygdala-based behaviors.

Fig. 1

Schematic representation of the FMR1 gene in a typical brain (a), in an FXS brain (b), and in the Fmr1 KO mouse (c). NLS = Nuclear localization signal; KH = hnRNP K-protein homology domains; NES = nuclear export signal; RGG = arginine-glycine-glycine. The FMR1 gene is composed of 17 exons. The normal number of CGG repeats in a typical brain produces FMRP (a). Full mutation of the FMR1 gene is reached when the 5′ enhancer is hypermethylated due to the presence of more than 200 CGG repeats (b). The Fmr1 KO mouse is generated by insertion of a neomycin cassette in exon 5, resulting in a lack of production of FMRP (c). NLS and NES domains allow FMRP to enter and exit the nucleus to bind and transport mRNAs. FMRP is a protein with multiple sites of interaction with mRNAs such as KH and RGG domains with differential affinity to mRNAs.

Fig. 2

FMRP is expressed in the amygdala and influences fear and stress response. FMRP is present at the synapse and regulates the translation of numerous proteins important for synaptic structure and function. Absence of FMRP at the synapse affects amygdala circuit function and therefore ultimately behavior.

Fig. 3

General scheme of connectivity between the amygdala and associated circuitry, and detailed organization of the flow of information within the amygdaloid complex. In the L and BL, local interneurons are part of feedforward and feedback circuits that control projection neuron outputs involved in fear conditioning. ITCl and ITCm relay feedforward inhibition to the BL and Ce, respectively. CeM output neurons are under inhibitory control originating in CeL. Intrinsic CeL inhibition may also participate in controlling CeL output. Ce neurons are mainly involved in processing fear responses by sending out information to different regions where different outputs of fear behavior are processed. AMY = Amygdala; BL = basolateral nucleus of the amygdala; BS = brain stem; CeL = laterocapsular subdivision of the central amygdala; CeM = medial subdivision of the central amygdala; Cx = cerebral cortex; OB = olfactory bulb; CG = central gray; ITCm = medial intercalated cell cluster; ITCl = lateral intercalated cell cluster; H = hippocampus; HYP = hypothalamus; L = lateral nucleus of the amygdala; LH = lateral hypothalamus; RPC = reticulopontis caudalis; T = thalamus; PVN = paraventricular nucleus.