Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3.

Cullin 3 (Cul3) gene, which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation, has been identified as a true high-risk factor for autism. Here, by combining behavioral, electrophysiological, and proteomic approaches, we have examined how Cul3 deficiency contributes to the etiology of different aspects of autism. Heterozygous mice with forebrain Cul3 deletion displayed autism-like social interaction impairment and sensory-gating deficiency. Region-specific deletion of Cul3 leads to distinct phenotypes, with social deficits linked to the loss of Cul3 in prefrontal cortex (PFC), and stereotypic behaviors linked to the loss of Cul3 in striatum. Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits. Large-scale profiling has identified sets of misregulated proteins resulting from Cul3 deficiency in different regions, including Smyd3, a histone methyltransferase involved in gene transcription. Inhibition or knockdown of Smyd3 in forebrain Cul3-deficient mice ameliorates social deficits and restores NMDAR function in PFC. These results have revealed for the first time a potential molecular mechanism underlying the manifestation of different autism-like behavioral deficits by Cul3 deletion in cortico-striatal circuits.

Deletion of Calcineurin in Schwann Cells Does Not Affect Developmental Myelination, But Reduces Autophagy and Delays Myelin Clearance after Peripheral Nerve Injury.

In the PNS, myelination occurs postnatally when Schwann cells (SCs) contact axons. Axonal factors, such as Neuregulin-1 Type III, trigger promyelinating signals that upregulate myelin genes. Neuregulin-1 Type III has been proposed to activate calcineurin signaling in immature SCs to initiate differentiation and myelination. However, little is known about the role of calcineurin in promyelinating SCs after birth. By creating a SC conditional KO of calcineurin B (CnBscko), we assessed the effects of CnB ablation on peripheral myelination after birth in both male and female mice. Surprisingly, CnBscko mice have minimal myelination defects, no alteration of myelin thickness, and normal KROX20 expression. In contrast, we did find a unique role for calcineurin in SCs after nerve injury. Following nerve crush, CnBscko mice have slower degeneration of myelin compared with WT mice. Furthermore, absence of CnB in primary SCs delays clearance of myelin debris. SCs clear myelin via autophagy and recent literature has demonstrated that calcineurin can regulate autophagy via dephosphorylation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. We demonstrate that loss of CnB reduces autophagic flux in primary SCs, indicating a possible mechanism for impaired myelin clearance. In addition, ablation of CnB impairs TFEB translocation to the nucleus 3 d after crush, suggesting that calcineurin may regulate autophagy in SCs via TFEB activation. Together, our data indicate that calcineurin is not essential for myelination but has a novel role in myelin clearance after injury.SIGNIFICANCE STATEMENT Our data offer a novel mechanism for activation of autophagy after peripheral nerve injury. Efficient clearance of myelin after injury by Schwann cells is important for axonal regrowth and remyelination, which is one reason why the PNS is significantly better at recovery compared with the CNS. Improved understanding of myelin clearance allows for the identification of pathways that are potentially accessible to increase myelin clearance and improve remyelination and recovery. Finally, this paper clarifies the role of calcineurin in Schwann cells and myelination.

αV integrins in Schwann cells promote attachment to axons, but are dispensable in vivo.

In the developing peripheral nervous system, Schwann cells (SCs) extend their processes to contact, sort, and myelinate axons. The mechanisms that contribute to the interaction between SCs and axons are just beginning to be elucidated. Using a SC-neuron coculture system, we demonstrate that Arg-Gly-Asp (RGD) peptides that inhibit αV -containing integrins delay the extension of SCs elongating on axons. αV integrins in SC localize to sites of contact with axons and are expressed early in development during radial sorting and myelination. Short interfering RNA-mediated knockdown of the αV integrin subunit also delays SC extension along axons in vitro, suggesting that αV -containing integrins participate in axo-glial interactions. However, mice lacking the αV subunit in SCs, alone or in combination with the potentially compensating α5 subunit, or the αV partners ß3 or ß8 , myelinate normally during development and remyelinate normally after nerve crush, indicating that overlapping or compensatory mechanisms may hide the in vivo role of RGD-binding integrins.

Histamine modulation of the basal ganglia circuitry in the development of pathological grooming.

Aberrant histaminergic function has been proposed as a cause of tic disorders. A rare mutation in the enzyme that produces histamine (HA), histidine decarboxylase (HDC), has been identified in patients with Tourette syndrome (TS). Hdc knockout mice exhibit repetitive behavioral pathology and neurochemical characteristics of TS, establishing them as a plausible model of tic pathophysiology. Where, when, and how HA deficiency produces these effects has remained unclear: whether the contribution of HA deficiency to pathogenesis is acute or developmental, and where in the brain the relevant consequences of HA deficiency occur. Here, we address these key pathophysiological questions, using anatomically and cellularly targeted manipulations in mice. We report that specific ablation or chemogenetic silencing of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus leads to markedly elevated grooming, a form of repetitive behavioral pathology, and to elevated markers of neuronal activity in both dorsal striatum and medial prefrontal cortex. Infusion of HA directly into the striatum reverses this behavioral pathology, confirming that acute HA deficiency mediates the effect. Bidirectional chemogenetic regulation reveals that dorsal striatum neurons activated after TMN silencing are both sufficient to produce repetitive behavioral pathology and necessary for the full expression of the effect. Chemogenetic activation of TMN-regulated medial prefrontal cortex neurons, in contrast, increases locomotion and not grooming. These data confirm the centrality of striatal regulation by neurotransmitter HA in the adult in the production of pathological grooming.

Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition.

The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons.

The basal ganglia have a central role in motor patterning, habits, motivated behaviors, and cognition as well as in numerous neuropsychiatric disorders. Receptors for histamine, especially the H3 receptor (H3R), are highly expressed in the striatum, the primary input nucleus of the basal ganglia, but their effects on this circuitry have been little explored. H3R interacts with dopamine (DA) receptors ex vivo; the nature and functional importance of these interactions in vivo remain obscure. We found H3R activation with the agonist R-(-)-α-methylhistamine to produce a unique time- and cell type-dependent profile of molecular signaling events in the striatum. H3 agonist treatment did not detectably alter extracellular DA levels or signaling through the cAMP/DARPP-32 signaling pathway in either D1- or D2-expressing striatal medium spiny neurons (MSNs). In D1-MSNs, H3 agonist treatment transiently activated MAPK signaling and phosphorylation of rpS6 and led to phosphorylation of GSK3ß-Ser9, a novel effect. Consequences of H3 activation in D2-MSNs were completely different. MAPK signaling was unchanged, and GSK3ß-Ser9 phosphorylation was reduced. At the behavioral level, two H3 agonists had no significant effect on locomotion or stereotypy, but they dramatically attenuated the locomotor activation produced by the D1 agonist SKF82958. H3 agonist co-administration blocked the activation of MAPK signaling and the phosphorylation of rpS6 produced by D1 activation in D1-MSNs, paralleling behavioral effects. In contrast, GSK3ß-Ser9 phosphorylation was seen only after H3 agonist treatment, with no interactive effects. H3R signaling has been neglected in models of basal ganglia function and has implications for a range of pathophysiologies.

Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation.

Microglia mediate neuroinflammation and regulate brain development and homeostasis. Microglial abnormalities are implicated in a range of neuropsychiatric pathology, including Tourette syndrome (TS) and autism. Histamine (HA) is both a neurotransmitter and an immune modulator. HA deficiency has been implicated as a rare cause of TS and may contribute to other neuropsychiatric conditions. In vitro studies suggest that HA can regulate microglia, but this has never been explored in vivo. We used immunohistochemistry to examine the effects of HA deficiency in histidine decarboxylase (Hdc) knockout mice and of HA receptor stimulation in wild-type animals. We find HA to regulate microglia in vivo, via the H4 receptor. Chronic HA deficiency in Hdc knockout mice reduces ramifications of microglia in the striatum and (at trend level) in the hypothalamus, but not elsewhere in the brain. Depletion of histaminergic neurons in the hypothalamus has a similar effect. Microglia expressing IGF-1 are particularly reduced, However, the microglial response to challenge with lipopolysacchariade (LPS) is potentiated in Hdc knockout mice. Genetic abnormalities in histaminergic signaling may produce a vulnerability to inflammatory challenge, setting the state for pathogenically dysregulated neuroimmune responses.

Microglial dysregulation in psychiatric disease.

Microglia, the brain's resident immune cells, are phagocytes of the macrophage lineage that have a key role in responding to inflammation and immune challenge in the brain. More recently, they have been shown to have a number of important roles beyond immune surveillance and response, including synaptic pruning during development and the support of adult neurogenesis. Microglial abnormalities have been found in several neuropsychiatric conditions, though in most cases it remains unclear whether these are causative or are a reaction to some other underlying pathophysiology. Here we summarize postmortem, animal, neuroimaging, and other evidence for microglial pathology in major depression, schizophrenia, autism, obsessive-compulsive disorder, and Tourette syndrome. We identify gaps in the existing literature and important areas for future research. If microglial pathology proves to be an important causative factor in these or other neuropsychiatric diseases, modulators of microglial function may represent a novel therapeutic strategy.

Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits.

Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (ChatCRECul3F/+) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF). Chemogenetic inhibition of BF cholinergic neurons in healthy mice induced similar social and cognitive deficits. Conversely, chemogenetic stimulation of BF cholinergic neurons in ChatCRECul3F/+ mice reversed abnormalities in sensory gating and cognition. Cortical hypofunction was also found after ChAT-specific Cul3 ablation and stimulation of cholinergic projections from the BF to the prefrontal cortex (PFC) mitigated cognitive deficits. Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC.

Lithium's effects on therapeutic targets and MRI biomarkers in Parkinson's disease: A pilot clinical trial.

Background: Lithium has a wide range of neuroprotective actions, has been effective in Parkinson's disease (PD) animal models and may account for the decreased risk of PD in smokers. Methods: This open-label pilot clinical trial randomized 16 PD patients to "high-dose" (n = 5, lithium carbonate titrated to achieve serum level of 0.4-0.5 mmol/L), "medium-dose" (n = 6, 45 mg/day lithium aspartate) or "low-dose" (n = 5, 15 mg/day lithium aspartate) lithium therapy for 24-weeks. Peripheral blood mononuclear cell (PBMC) mRNA expression of nuclear receptor-related-1 (Nurr1) and superoxide dismutase-1 (SOD1) were assessed by qPCR in addition to other PD therapeutic targets. Two patients from each group received multi-shell diffusion MRI scans to assess for free water (FW) changes in the dorsomedial nucleus of the thalamus and nucleus basalis of Meynert, which reflect cognitive decline in PD, and the posterior substantia nigra, which reflects motor decline in PD. Results: Two of the six patients receiving medium-dose lithium therapy withdrew due to side effects. Medium-dose lithium therapy was associated with the greatest numerical increases in PBMC Nurr1 and SOD1 expression (679% and 127%, respectively). Also, medium-dose lithium therapy was the only dosage associated with mean numerical decreases in brain FW in all three regions of interest, which is the opposite of the known longitudinal FW changes in PD. Conclusion: Medium-dose lithium aspartate therapy was associated with engagement of blood-based therapeutic targets and improvements in MRI disease-progression biomarkers but was poorly tolerated in 33% of patients. Further PD clinical research is merited examining lithium's tolerability, effects on biomarkers and potential disease-modifying effects.

White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology.

Introduction: An inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. Hdc, which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine. Hdc knockout mice (Hdc-KO) functionally recapitulate this mutation and exhibit behavioral and neurochemical abnormalities that parallel those seen in patients with TS. Materials and methods: We performed exploratory RNA-seq to identify pathological alterations in several brain regions in Hdc-KO mice. Findings were corroborated with RNA and protein quantification, immunohistochemistry, and ex vivo brain imaging using MRI. Results: Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain ex vivo diffusion tensor imaging (DTI), which revealed reduced fractional anisotropy (FA) in the dorsal striatum. Discussion: While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. The Hdc-KO model may represent a powerful system in which to examine the developmental mechanisms underlying this abnormality.

ACTL6a coordinates axonal caliber recognition and myelination in the peripheral nerve.

Cells elaborate transcriptional programs in response to external signals. In the peripheral nerves, Schwann cells (SC) sort axons of given caliber and start the process of wrapping their membrane around them. We identify Actin-like protein 6a (ACTL6a), part of SWI/SNF chromatin remodeling complex, as critical for the integration of axonal caliber recognition with the transcriptional program of myelination. Nuclear levels of ACTL6A in SC are increased by contact with large caliber axons or nanofibers, and result in the eviction of repressive histone marks to facilitate myelination. Without Actl6a the SC are unable to coordinate caliber recognition and myelin production. Peripheral nerves in knockout mice display defective radial sorting, hypo-myelination of large caliber axons, and redundant myelin around small caliber axons, resulting in a clinical motor phenotype. Overall, this suggests that ACTL6A is a key component of the machinery integrating external signals for proper myelination of the peripheral nerve.

Wrestling and Wrapping: A Perspective on SUMO Proteins in Schwann Cells.

Schwann cell development and peripheral nerve myelination are finely orchestrated multistep processes; some of the underlying mechanisms are well described and others remain unknown. Many posttranslational modifications (PTMs) like phosphorylation and ubiquitination have been reported to play a role during the normal development of the peripheral nervous system (PNS) and in demyelinating neuropathies. However, a relatively novel PTM, SUMOylation, has not been studied in these contexts. SUMOylation involves the covalent attachment of one or more small ubiquitin-like modifier (SUMO) proteins to a substrate, which affects the function, cellular localization, and further PTMs of the conjugated protein. SUMOylation also regulates other proteins indirectly by facilitating non-covalent protein-protein interaction via SUMO interaction motifs (SIM). This pathway has important consequences on diverse cellular processes, and dysregulation of this pathway has been reported in several diseases including neurological and degenerative conditions. In this article, we revise the scarce literature on SUMOylation in Schwann cells and the PNS, we propose putative substrate proteins, and we speculate on potential mechanisms underlying the possible involvement of this PTM in peripheral myelination and neuropathies.

Rac1 and Rac3 have opposite functions in Schwann cells during developmental myelination.

Small Rho GTPases such as Cdc42 and Rac1 regulate peripheral myelination during development. Deletion of Rac1 in Schwann cell conditional knockout mice causes a delay in the process of radial sorting, followed by hypomyelination as well as defective PAK1 activation and high number of immature Oct6+ Schwann cells. Rac3 has been shown to have redundant, specific and even opposite functions to Rac1 depending on the cell type, age and other factors. In neuronal cells, evidence suggests that Rac3 may oppose Rac1 by disrupting PAK1-GIT1-Paxillin signaling thus preventing cell differentiation and extension of lamellipodia. Therefore, we tested if these Rho GTPases have similar or opposite functions in Schwann cells, by deleting the genes for both proteins in mice during peripheral myelination. At P30, global deletion of Rac3 alleviates the developmental defects on axonal sorting and hypomyelination that are caused by Schwann cell conditional ablation of Rac1. Moreover, Rac3 deletion also reverses the arrest of Schwann cells at the Oct6+ stage and ameliorates the defects in PAK1 phosphorylation observed in Rac1 deficient mice. This partial rescue of the phenotype declines later on with aging. Since double transgenic animals showed dysmyelination without axonal degeneration at P60, we postulate that this deterioration is not likely due to loss of Rac3 in neurons, but it seems to be a Schwann cell-specific defect in the maintenance of myelin.

Schwann cell interactions during the development of the peripheral nervous system.

Schwann cells play a critical role in the development of the peripheral nervous system (PNS), establishing important relationships both with the extracellular milieu and other cell types, particularly neurons. In this review, we discuss various Schwann cell interactions integral to the proper establishment, spatial arrangement, and function of the PNS. We include signals that cascade onto Schwann cells from axons and from the extracellular matrix, bidirectional signals that help to establish the axo-glial relationship and how Schwann cells in turn support the axon. Further, we speculate on how Schwann cell interactions with other components of the developing PNS ultimately promote the complete construction of the peripheral nerve.

Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity.

OBJECTIVE: Pediatric obsessive-compulsive disorder (OCD) sometimes appears rapidly, even overnight, often after an infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or PANDAS, describes such a situation after infection with Streptococcus pyogenes. PANDAS may result from induced autoimmunity against brain antigens, although this remains unproven. Pilot work suggests that IgG antibodies from children with PANDAS bind to cholinergic interneurons (CINs) in the striatum. CIN deficiency has been independently associated with tics in humans and with repetitive behavioral pathology in mice, making it a plausible locus of pathology. The authors sought to replicate and extend earlier work and to investigate the cellular effects of PANDAS antibodies on cholinergic interneurons. METHODS: Binding of IgG to specific neurons in human and mouse brain slices was evaluated ex vivo after incubation with serum from 27 children with rigorously characterized PANDAS, both at baseline and after intravenous immunoglobulin (IVIG) treatment, and 23 matched control subjects. Binding was correlated with symptom measures. Neural activity after serum incubation was assessed in mouse slices using molecular markers and electrophysiological recording. RESULTS: IgG from children with PANDAS bound to CINs, but not to several other neuron types, more than IgG from control subjects, in three independent cohorts of patients. Post-IVIG serum had reduced IgG binding to CINs, and this reduction correlated with symptom improvement. Baseline PANDAS sera decreased activity of striatal CINs, but not of parvalbumin-expressing GABAergic interneurons, and altered their electrophysiological responses, in acute mouse brain slices. Post-IVIG PANDAS sera and IgG-depleted baseline sera did not alter the activity of striatal CINs. CONCLUSIONS: These findings provide strong evidence for striatal CINs as a critical cellular target that may contribute to pathophysiology in children with rapid-onset OCD symptoms, and perhaps in other conditions.

Modulation of endothelial and neuronal nitric oxide synthases during learning of an operant conditioning task.

Nitric oxide (NO) promotes plasticity and it is essential for learning, the NO synthases involved in these events are the endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) isoforms. The aim of this study was to study transcription, protein expression and enzymatic activity of eNOS and nNOS in the prefrontal cortex and the hippocampus during learning an operant conditioning task. Animals were considered incompletely trained (IT) when performed between 50% and 65% of responses, whereas animals were considered trained when reached 100% of responses with a latency time lower than 5 s. Following training session animals were killed and we quantified mRNA levels by Real Time RT-PCR, protein expression by western blot and enzymatic activity. eNOS and nNOS mRNA levels were only incremented in IT group. On the contrary, protein expression of both isoforms were augmented during all learning process. Moreover, we also found that eNOS and nNOS synthase activity were incremented in IT group and in trained group. Here, we showed that during learning there is a differential regulation of eNOS and nNOS in the prefrontal cortex and hippocampus and that NO could be acting as a promoter of plasticity.

Fluoxetine directly counteracts the adverse effects of chronic stress on T cell immunity by compensatory and specific mechanisms.

Chronic stress and depression are widely known to down-regulate the immune system, and several antidepressants can reverse this impairment, with or without effects in normal subjects. Although the central nervous system is undoubtedly involved in these events, some psychotropic drugs can also exert direct effects on lymphoid cells. We have recently shown that the antidepressant fluoxetine enhances T cell proliferation and T(H)1 cytokine production in vivo, without changes on CD4/CD8 subsets. In vitro, a direct action of fluoxetine upon T lymphocyte reactivity by complex mechanisms was also described. In another work, we also found that chronic stress reduces T cell mediated immunity, namely a decrease of T cell response to mitogens, T(H)1 cytokine production and CD4+-but not CD8+--T lymphocytes. Here we investigated the effects of fluoxetine on chronic stress-driven immune system depression. We found that fluoxetine restored T cell proliferation and interleukin-2, interferon-gamma and tumor necrosis factor-alpha production by compensatory mechanisms. In addition, CD4/CD8 ratio was also normalized by antidepressant administration, but this seems to be a non-compensatory effect associated specifically to stress. No changes were observed in other lymphoid cells, i.e. natural killer cells and B lymphocytes. Finally, we observed that fluoxetine is able to reverse T cell reactivity impairment in vitro by a direct action at clinically relevant doses. These results highlight the relevance of pharmacological treatment of stress and depression, and may help to begin elucidating the complex events triggered--directly and/or indirectly--by antidepressants in non-neuronal cell types.

Immune-endocrine interactions in autoimmune thyroid diseases.

Autoimmune thyroid diseases (AITD) are the most common organ-specific autoimmune disorders affecting approximately 5% of the overall population. An aberrant interaction between abnormal thyrocytes, abnormal antigen-presenting cells and abnormal T cells forms the basis for the atypical autoimmune reaction targeting thyroid antigens. It was proposed that nongenetic (environmental and hormonal) factors play a crucial etiological role in AITD development, through altering immune-endocrine interactions. The most outstanding fact is that in genetically predisposed individuals, the disruption of these neuroendocrine-immune interactions by environmental factors results in thyroid autoimmune dysfunction. These interactions are able to incline the balance between Th1-Th2 immune response toward one side, resulting in a Th1-cell-mediated autoimmune reaction with thyrocyte destruction and hypothyroidism in Hashimoto's thyroiditis but to a hyperreactive Th2-mediated humoral response against TSH receptor with stimulatory antibodies leading to Graves' disease hyperthyroidism. In this review the main mechanisms involved are summarized. In this sense, the participation of stress-mediated activation of the sympathoadrenal system and hypothalamic-pituitary-adrenal axis, the hormonal changes occurring during pregnancy and postpartum acting on antigen-presenting cells and influencing, in this way, the balance of the immune status are shown to participate in AITD etiology. The possibility that altered levels of thyroid hormones during the course of the AITD may alter immune function is also discussed.

Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology.

Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising model of this pathophysiology. How alterations in the histamine system lead to neuropsychiatric disease, however, remains unclear. The H3R histamine receptor is elevated in the striatum of Hdc KO mice, and H3R agonists, acting in the dorsal striatum, trigger tic-like movements in the model. In wild-type mice, H3R in the dorsal striatum differentially regulates mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling in D1R dopamine receptor-expressing striatonigral medium spiny neurons (dMSNs) and D2R dopamine receptor-expressing striatopallidal MSNs (iMSNs), respectively. We examined the effects of H3R agonist treatment on MSN signaling in the Hdc-KO model. In dMSNs, MAPK signaling was elevated at baseline in the Hdc-KO model, resembling what is seen after H3R activation in WT animals. Similarly, in iMSNs, Akt phosphorylation was reduced at baseline in the KO model, resembling what is seen after H3R activation in WT animals. H3R activation in Hdc-KO mice further enhanced the baseline effect on Akt phosphorylation in iMSNs but attenuated the abnormality in MAPK signaling in dMSNs. These observations support the hypothesis that constitutive activity of upregulated H3R receptors in the Hdc-KO model mediates the observed alterations in baseline MSN signaling; but further activation of H3R, which produces tic-like repetitive movements in the model, has more complex effects.