Inter‐α‐inhibitor deficiency in the mouse is associated with alterations in anxiety‐like behavior, exploration and social approach

Abstract

In recent years, several genome-wide association studies have identified candidate regions for genetic susceptibility in major mood disorders. Most notable are regions in a locus in chromosome 3p21, encompassing the genes NEK4-ITIH1-ITIH3-ITIH4. Three of these genes represent heavy chains of the composite protein inter-α-inhibitor (IαI). In order to further establish associations of these genes with mood disorders, we evaluated behavioral phenotypes in mice deficient in either Ambp/bikunin, which is necessary for functional ITIH1 and ITIH3 complexes, or in Itih4, the gene encoding the heavy chain Itih4. We found that loss of Itih4 had no effect on the behaviors tested, but loss of Ambp/bikunin led to increased anxiety-like behavior in the light/dark and open field tests and reduced exploratory activity in the elevated plus maze, light/dark preference and open field tests. Ambp/bikunin knockout mice also exhibited a sex-dependent exaggeration of acoustic startle responses, alterations in social approach during a three-chamber choice test, and an elevated fear conditioning response. These results provide experimental support for the role of ITIH1/ITIH3 in the development of mood disorders.

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…Similarly, the dysregulation of Ina expression and of Il33 in Table 1 for the CAG100-KIN were similarly reported for ALS [70, 106]. The progressive decrease of Unc13c mRNA levels in Table 1 reflects the specific motor deficits of these mice, in view of its key role in cerebellar parallel fibers for fast reflexes and motor learning [9, 128]; the depletion of Slc6a11 encoding the GABA-transporter-3, and of Gabrb2 encoding the GABA-A-receptor-beta-2, in CAG100-KIN clearly mirrors the dysfunction of GABA-ergic signaling in the spinal dorsal horn and in cerebellar Purkinje cells [63, 86]; the deficiency of Itih3 -encoded protein complexes was documented in Table 1 and occurs similarly after denervation, leading to diminished exploration and anxiety-like behavior in mice [21, 61, 134].…”

Ontogeny of inter‐alpha inhibitor protein (IAIP) expression in human brain

“…In the brain, we have shown that endogenous IAIPs were reduced 4 hr after ischemia in the fetal sheep, suggesting that changes in endogenous IAIPs could participate in the response to brain ischemia (Spasova et al, ), and findings showing decreased plasma levels of inter‐alpha trypsin inhibitor heavy chain 4 in adult patients with ischemic stroke agree with our previous findings (Kashyap et al, ). In addition, recent work examined behavioral phenotypes in mice deficient in Ambp/bikunin, the light chain of IAIPs (Goulding et al, ). The loss of Ambp/bikunin resulted in augmented anxiety‐like behavior, decreased exploratory activity, increased sex‐dependent acoustic startle responses, and alterations in social approach in mice suggesting a role for the heavy chains, ITIH1/ITIH3, in the development of mood disorders (Goulding et al, ).…”

“…In addition, recent work examined behavioral phenotypes in mice deficient in Ambp/bikunin, the light chain of IAIPs (Goulding et al, ). The loss of Ambp/bikunin resulted in augmented anxiety‐like behavior, decreased exploratory activity, increased sex‐dependent acoustic startle responses, and alterations in social approach in mice suggesting a role for the heavy chains, ITIH1/ITIH3, in the development of mood disorders (Goulding et al, ). Polymorphisms of inter‐alpha inhibitor heavy chain 3 are also associated with increased incidences of psychiatric disorders and suicide attempts in patients (Hamshere et al, ; Sasayama et al, ).…”

“…GFAP-stained astrocytes (red, arrows), IAIP staining (green, arrows), and IAIP-expressing GFAP-stained astrocytes (red green blue, Merge, arrowheads) were identified in both the preterm infant at 24 weeks of gestation and the adult. Scale bar = 10 μm startle responses, and alterations in social approach in mice suggesting a role for the heavy chains, ITIH1/ITIH3, in the development of mood disorders (Goulding et al, 2019). Polymorphisms of inter-alpha inhibitor heavy chain 3 are also associated with increased incidences of psychiatric disorders and suicide attempts in patients (Hamshere et al, 2013;Sasayama et al, 2014).…”

“…Studies have also suggested that IAIPs could be important in neuroplasticity (Duman, Aghajanian, Sanacora, & Krystal, 2016;Gaudet, Lim, Stonestreet, & Threlkeld, 2016;Goldschmied & Gehrman, 2019;Normann, Schmitz, Furmaier, Doing, & Bach, 2007;Popoli, Gennarelli, & Racagni, 2002). Other studies have reported that genetically determined variants in the heavy chains of IAIPs are related to psychiatric disorders including schizophrenia and bipolar disorders (Brandl et al, 2016;Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013; Hamshere et al, 2013;Sasayama et al, 2014;Schizophrenia Psychiatric Genome-Wide Association Study Consortium, 2011) and that mice deficient in bikunin (Ambp/bikunin knockout mice) exhibit specific behavioral phenotypes such as increased anxiety-like behavior (Goulding et al, 2019). Taken together, these findings suggest that endogenous IAIPs could have important roles in a variety of brain-related abnormalities.…”