Soluble Cytokine Receptors (sIL-2Rα, sIL-2Rβ) Induce Subunit-Specific Behavioral Responses and Accumulate in the Cerebral Cortex and Basal Forebrain

Abstract

Soluble cytokine receptors are normal constituents of body fluids that regulate peripheral cytokine and lymphoid activity. Levels of soluble IL-2 receptors (sIL-2R) are elevated in psychiatric disorders linked with autoimmune processes, including ones in which repetitive stereotypic behaviors and motor disturbances are present. However, there is no evidence that sIL-2Rs (or any peripheral soluble receptor) induce such behavioral changes, or that they localize in relevant brain regions. Here, we determined in male Balb/c mice the effects of single peripheral injections of sIL-2Rα or sIL-2Rβ (0–2 µg/male Balb/c mouse; s.c.) on novelty-induced ambulatory activity and stereotypic motor behaviors. We discovered that sIL-2Rα increased the incidence of in-place stereotypic motor behaviors, including head up head bobbing, rearing/sniffing, turning, and grooming behavior. A wider spectrum of behavioral changes was evident in sIL-2Rβ-treated mice, including increases in vertical and horizontal ambulatory activity and stereotypic motor movements. To our knowledge, this is the first demonstration that soluble receptors induce such behavioral disturbances. In contrast, soluble IL-1 Type-1 receptors (0–4 µg, s.c.) didn't appreciably affect these behaviors. We further demonstrated that sIL-2Rα and sIL-2Rβ induced marked increases in c-Fos in caudate-putamen, nucleus accumbens and prefrontal cortex. Anatomical specificity was supported by the presence of increased activity in lateral caudate in sIL-2Rα treated mice, while sIL-2Rβ treated mice induced greater c-Fos activity in prepyriform cortex. Moreover, injected sIL-2Rs were widely distributed in regions that showed increased c-Fos expression. Thus, sIL-2Rα and sIL-2Rβ induce marked subunit- and soluble cytokine receptor-specific behavioral disturbances, which included increases in the expression of ambulatory activity and stereotypic motor behaviors, while inducing increased neuronal activity localized to cortex and striatum. These findings suggest that sIL-2Rs act as novel immune-to- brain messengers and raise the possibility that they contribute to the disease process in psychiatric disorders in which marked increases in these receptors have been reported.

Animal models of tic disorders: A translational perspective

“…Treatment of pregnant female mice with IL-2 during mid-gestation results in behavioral alterations, including self-grooming and rearing (Ponzio et al, 2007); conversely, IL6 treatment results in decreased PPI (Smith et al, 2007). Furthermore, recent evidence has shown that treatment with specific subunits of the soluble receptors for these cytokines results in stereotyped movements and multiple alterations of locomotor activity (Patel et al, 2012; Zalcman et al, 2012). …”

Immune-mediated animal models of Tourette syndrome

“…Another soluble cytokine receptor that is elevated in some autoimmune and neuropsychiatric disorders, sIL-6R, produces effects similar to those observed with sIL-2R (Zalcman et al, 2012) in BALB/c mice (Patel et al, 2012). Vertical stereotypies and novelty-associated exploratory motor behaviors increased within 80 minutes of injection of recombinant human sIL-6Rα, a form that is reactive with both human and mouse IL-6; effects were exacerbated when sIL-6Rα administration was followed by the dopamine uptake inhibitor GBR 12909.…”

“…Soluble cytokine receptors play important roles as regulators of cytokine and lymphocyte activity and are increased in some autoimmune conditions and psychiatric disorders. Balb/c mice receiving single subcutaneous (sc) injections of soluble IL-2 receptors (sIL-2R) α or β showed increased repetitive head bobbing, grooming and rearing/sniffing behaviors as well as other stereotypic behaviors in the vertical and horizontal planes (Zalcman et al, 2012). Effects were most prominent with administration of sIL-2Rβ as compared to sIL-2Rα and behavioral profiles differed slightly for the two sIL-2R subtypes.…”

“…Vertical stereotypies and novelty-associated exploratory motor behaviors increased within 80 minutes of injection of recombinant human sIL-6Rα, a form that is reactive with both human and mouse IL-6; effects were exacerbated when sIL-6Rα administration was followed by the dopamine uptake inhibitor GBR 12909. Peripherally-administered sIL-6Rα accumulated in cortico-striatal-thalamo-cortical (CSTC) regions - circuitry implicated as the neuroanatomical substrate of motor stereotypies - in a distribution pattern overlapping with but not identical to that observed with administration of sIL-2R (Zalcman et al, 2012). The brain distribution of injected sIL-6R also co-localized with the IL-6 trans-membrane signaling protein gp130 in nucleus accumbens, caudate-putamen, thalamus and motor and infralimbic cortex; the source of this accumulated sIL-6R was able to be unambiguously identified in immunohistochemical experiments as the exogenous recombinant sIL-6Rα as opposed to any endogenous mouse IL-6R that may be found in brain by using anti-human IL-6Rα antibodies that do not detect mouse IL-6R.…”

“…The majority of the animal models described here that used extra-CNS exposures (either through tail vein or at subcutaneous sites) depended on the inclusion of agents associated with BBB compromise. The exceptions are the rhesus monkey model described by Amaral and coworkers (Martin et al, 2008) and several mouse model studies by Zalcman and colleagues (Patel et al, 2012; Ponzio et al, 2007; Zalcman et al, 1994; Zalcman et al, 1998; Zalcman, 2002; Zalcman et al, 2012). Further examination of the means by which antibodies enter CNS across the BBB are required.…”