Estrogen Receptor β Agonist Attenuates Endoplasmic Reticulum Stress-Induced Changes in Social Behavior and Brain Connectivity in Mice

Abstract

Impaired social interaction is a key feature of several major psychiatric disorders including depression, autism, and schizophrenia. While, anatomically, the prefrontal cortex (PFC) is known as a key regulator of social behavior, little is known about the cellular mechanisms that underlie impairments of social interaction. One etiological mechanism implicated in the pathophysiology of the aforementioned psychiatric disorders is cellular stress and consequent adaptive responses in the endoplasmic reticulum (ER) that can result from a variety of environmental and physical factors. The ER is an organelle that serves essential roles in protein modification, folding, and maturation of proteins; however, the specific role of ER stress in altered social behavior is unknown. In this study, treatment with tunicamycin, an ER stress inducer, enhanced the phosphorylation level of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) and increased X-box-binding protein 1 (XBP1) mRNA splicing activity in the mouse PFC, whereas inhibition of IRE1/XBP1 pathway in PFC by a viral particle approach attenuated social behavioral deficits caused by tunicamycin treatment. Reduced estrogen receptor beta (ERβ) protein levels were found in the PFC of male mice following tunicamycin treatment. Pretreatment with an ERβ specific agonist, ERB-041 significantly attenuated tunicamycin-induced deficits in social behavior, and activation of IRE1/XBP1 pathway in mouse PFC. Moreover, ERB-041 inhibited tunicamycin-induced increases in functional connectivity between PFC and hippocampus in male mice. Together, these results show that ERβ agonist attenuates ER stress-induced deficits in social behavior through the IRE-1/XBP1 pathway.

Genetic mutations in Ca2+ signaling alter dendrite morphology and social approach in juvenile mice

“…For example, early life stress caused by maternal separation increased apical dendritic branch number and length of pyramidal neurons in the medial prefrontal cortex of female juvenile rats, and these morphological outcomes coincided with deficits in social interactions . Similarly, in a model of endoplasmic reticulum stress, adult male mice exhibit decreased social behavior coincident with hyperconnectivity in the neural circuit from the medial prefrontal cortex to the dorsal hippocampus as measured by implanted depth electrodes . However, our results also indicate that alterations in dendritic morphology do not necessarily predict behavioral outcomes or vice versa.…”

“…76 Similarly, in a model of endoplasmic reticulum stress, adult male mice exhibit decreased social behavior coincident with hyperconnectivity in the neural circuit from the medial prefrontal cortex to the dorsal hippocampus as measured by implanted depth electrodes. 61 However, our results also indicate that alterations in dendritic morphology do not necessarily predict behavioral outcomes or vice versa. We found no difference in social behavior between WT and CGG juvenile mice despite evidence of subtle differences in dendritic morphology.…”

“…Furthermore, changes in neural organization and density in the hippocampus have been correlated with social deficits in a rat model of autism . These brain regions also serve as anatomic substrates of social behavior in humans and preclinical models …”

“…58 These brain regions also serve as anatomic substrates of social behavior in humans 59,60 and preclinical models. [61][62][63] Sholl plots and representative images of the basilar dendritic arbor of Golgi-stained pyramidal CA1 hippocampal neurons for each sex and genotype are shown in Figure 1A-C. Genotype differences were limited to male neurons and included a significant increase in the distance from the soma of the maximum number of dendritic intersections in T4826I male neurons compared to either WT (P = 0.0028) or DM (P = 0.0128) neurons ( Figure 1D,E, Table 2; Table S2). There were no significant differences between genotypes with respect to the maximum number of dendritic intersections ( Figure 1F,G) or the total area under the Sholl curve ( Figure 1H,I) in male or female hippocampal neurons.…”

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders

“…Activation of Protein kinase A (PKA) via cyclic AMP by different agents in the brain can in turn influence IRE1α (Saito et al, 2018 ). Inhibition of IRE1α ameliorated the social behavior deficits, a commonly observed trait in some neuropsychiatric disorders (Crider et al, 2018 ). Upon UPR induction, ATF6 is translocated to the Golgi apparatus for further processing by Site-1 and Site-2 proteases (S1P and S2P, respectively), leading to the release of amino-terminal fragment ATF6f with transcription factor functions.…”