Tackling hypo and hyper sensory processing heterogeneity in autism: From clinical stratification to genetic pathways.

As an integral part of autism spectrum symptoms, sensory processing issues including both hypo and hyper sensory sensitivities. These sensory specificities may result from an excitation/inhibition imbalance with a poorly understood of their level of convergence with genetic alterations in GABA-ergic and glutamatergic pathways. In our study, we aimed to characterize the hypo/hyper-sensory profile among autistic individuals. We then explored its link with the burden of deleterious mutations in a subset of individuals with available whole-genome sequencing data. To characterize the hypo/hyper-sensory profile, the differential Short Sensory Profile (dSSP) was defined as a normalized and centralized hypo/hypersensitivity ratio from the Short Sensory Profile (SSP). Including 1136 participants (533 autistic individuals, 210 first-degree relatives, and 267 controls) from two independent study samples (PARIS and LEAP), we observed a statistically significant dSSP mean difference between autistic individuals and controls, driven mostly by a high dSSP variability, with an intermediated profile represented by relatives. Our genetic analysis tended to associate the dSSP and the hyposensitivity with mutations of the GABAergic pathway. The major limitation was the dSSP difficulty to discriminate subjects with a similar quantum of hypo- and hyper-sensory symptoms to those with no such symptoms, resulting both in a similar ratio score of 0. However, the dSSP could be a relevant clinical score, and combined with additional sensory descriptions, genetics and endophenotypic substrates, will improve the exploration of the underlying neurobiological mechanisms of sensory processing differences in autism spectrum.

Altered glutamatergic and inflammatory pathways promote glioblastoma growth, invasion, and seizures: An overview.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain cancer. Drug-resistant seizures and cognitive impairments often accompany the invasion of the neocortex by the GBM cells. Recent studies suggest that seizures and glioma share common pathogenic mechanisms and may influence each other. One explanation for the close link between the two conditions is elevated glutamate in the tumor microenvironment (TME) due to an increased expression of the cystine-glutamate transporter with ensuing overactivity of glutamatergic signaling. Excess glutamate in the TME also encourages the polarization of pro-inflammatory tumor-associated macrophages to an anti-inflammatory state causing TME immunosuppression and facilitating tumor invasion. Besides, the recently discovered glutamatergic neurogliomal synapses, partially via their influence on calcium communication in microtube-connected tumor cell networks, drive the progression of GBM by stimulating glioma invasion and growth. Moreover, neuroinflammatory pathways have been shown to have several points of intersection with glutamatergic signaling in the TME, further promoting both epileptogenesis and oncogenesis. Future studies identifying pharmacotherapeutics targeting these elements is an extremely attractive therapeutic strategy for GBM, for which very little therapeutic progress has been made in the past two decades.

Is depression the missing link between inflammatory mediators and cancer?

Patients with cancer are at greater risk of developing depression in comparison to the general population and this is associated with serious adverse effects, such as poorer quality of life, worse prognosis and higher mortality. Although the relationship between depression and cancer is now well established, a common underlying pathophysiological mechanism between the two conditions is yet to be elucidated. Existing theories of depression, based on monoamine neurotransmitter system dysfunction, are insufficient as explanations of the disorder. Recent advances have implicated neuroinflammatory mechanisms in the etiology of depression and it has been demonstrated that inflammation at a peripheral level may be mirrored centrally in astrocytes and microglia serving to promote chronic levels of inflammation in the brain. Three major routes to depression in cancer in which proinflammatory mediators are implicated, seem likely. Activation of the kynurenine pathway involving cytokines, increases tryptophan catabolism, resulting in diminished levels of serotonin which is widely acknowledged as being the hallmark of depression. It also results in neurotoxic effects on brain regions thought to be involved in the evolution of major depression. Proinflammatory mediators also play a crucial role in impairing regulatory glucocorticoid mediated feedback of the hypothalamic-pituitary-adrenal axis, which is activated by stress and considered to be involved in both depression and cancer. The third route is via the glutamatergic pathway, whereby glutamate excitotoxicity may lead to depression associated with cancer. A better understanding of the mechanisms underlying these dysregulated and other newly emerging pathways may provide a rationale for therapeutic targeting, serving to improve the care of cancer patients.

WNT/ß-catenin pathway and circadian rhythms in obsessive-compulsive disorder.

The neuropsychiatric disease named obsessive-compulsive disorder is composed by obsessions and/or compulsions. Obsessive-compulsive disorder etiologies are undefined. However, numerous mechanisms in several localizations are implicated. Some studies showed that both glutamate, inflammatory factors and oxidative stress could have main functions in obsessive-compulsive disorder. Glycogen synthase kinase-3ß, the major negative controller of the WNT/ß-catenin pathway is upregulated in obsessive-compulsive disorder. In obsessive-compulsive disorder, some studies presented the actions of the different circadian clock genes. WNT/ß-catenin pathway and circadian clock genes appear to be intricate. Thus, this review focuses on the interaction between circadian clock genes and the WNT/ß-catenin pathway in obsessive-compulsive disorder.

Src family kinases activity is required for transmitting purinergic P2X7 receptor signaling in cortical spreading depression and neuroinflammation.

BACKGROUND: Purinergic P2X7 receptor plays an important role in migraine pathophysiology. Yet precise molecular mechanism underlying P2X7R signaling in migraine remains unclear. This study explores the hypothesis that P2X7 receptor transmits signaling to Src family kinases (SFKs) during cortical spreading depression (CSD) and neuroinflammation after CSD. METHODS: CSD was recorded using electrophysiology in rats and intrinsic optical imaging in mouse brain slices. Cortical IL-1ß and TNFα mRNA levels were detected using qPCR. Glutamate release from mouse brain slices was detected using glutamate assay. RESULTS: The data showed that deactivation of SFKs by systemic injection of PP2 reduced cortical susceptibility to CSD in rats and CSD-induced IL-1ß and TNF-α gene expression in rat ipsilateral cortices. Consistently, in mouse brain slices, inhibition of SFKs activity by saracatinib and P2X7 receptor by A740003 similarly reduced cortical susceptibility to CSD. When the interaction of P2X7 receptor and SFKs was disrupted by TAT-P2X7, a marked reduction of cortical susceptibility to CSD, IL-1ß gene expression and glutamate release after CSD induction were observed in mouse brain slices. The reduced cortical susceptibility to CSD by TAT-P2X7 was restored by NMDA, and disrupting the Fyn-NMDA interaction using TAT-Fyn (39-57) but not disrupting Src-NMDA receptor interaction using TAT-Src (40-49) reduced cortical susceptibility to CSD. Furthermore, activation of P2X7 receptor by BzATP restored the TAT-Fyn (39-57)-reduced cortical susceptibility to CSD. CONCLUSION: This study reveals that SFKs activity transmits P2X7 receptor signaling to facilitate CSD propagation via glutamatergic pathway and promote neuroinflammation, which is of particular relevance to migraine.

Effects of safinamide on REM sleep behavior disorder in Parkinson disease: A randomized, longitudinal, cross-over pilot study.

BACKGROUND: Rapid Eye Movement sleep behavior disorder (RBD) is characterized by dream enactment and loss of muscle atonia during REM-sleep. RBD as a premotor feature occurred souvent in patients who develop Parkinson's disease. The glutamatergic, glycinergic, and GABA-ergic systems appear to play a crucial role in the pathogenesis of RBD. METHODS: The present exploratory longitudinal cross-over study aimed to observe the effect of safinamide on RBD symptoms. Thirty patients with PD and RBD were randomized into two groups (15 subjects each), those that received for a period of 3-months safinamide (50 mg/die) in addition (Group A + ) or in absence (Group B - ) to the usual antiparkinsonian therapy. Patients exploring the clinical and video-polysomnographic changes occurred during this pharmacological therapy. RESULTS: Twenty-two of 30 patients reported clear improvement in symptoms during safinamide treatment, and 16 were absolutely free from clinical RBD-symptoms at the end of the treatment. Eight patients reported slight improvement in RBD-symptoms. In 6/30 patients no substantial improvement was recorded about clinical RBD-symptoms had frightening dreams or from the bed after 1-week of treatment. In addition, after safinamide, the mean UPDRS-II and III scores decreased, while PDSS-2 score indicating an improvement in both motor symptoms and nocturnal sleep features. A significant reduction of sleep behavior disorder by questionnaire-Hong Kong-score (RBDQ-HS), mainly for two individual RBDQ-HK-items (dream related movements and failing out of bed) was registered. CONCLUSIONS: This pilot study indicated that safinamide is well tolerated and improves RBD-symptom in parkinsonian.

Antinociceptive activity of puberulin and choisyine from ethanol extract of Choisya ternata Kunth var. Sundance.

Choisya ternata Kunth variety Sundance (CTS) is a plant used in traditional medicine in North America, especially in Mexico. The present study evaluated the antinociceptive activity of the crude ethanolic extract of CTS leaves and tested its isolated compounds puberulin (Pu) and choisyine (Ch). An antinociceptive effect was observed after treatment with CTS extract and the isolated compounds Pu and Ch. Mice orally pre-treated with CTS extract (10, 30 or 100 mg/kg), Pu or Ch (0.3, 1 or 3 mg/kg) were less sensitive to chemical and thermal algesic agents in different animal models (formalin-, glutamate- and capsaicin-induced licking response tests and hot plate test). In addition, an antagonist of the opioid receptor was able to reverse the antinociceptive effect observed for the CTS extract and the isolated substance Ch, but it did not inhibit the effect of Pu. The cholinergic pathway was found to be involved in this antinociceptive effect for the CTS extract and Ch but has no participation in the Pu antinociceptive activity.

Lithium and Atypical Antipsychotics: The Possible WNT/ß Pathway Target in Glaucoma.

Glaucoma is a progressive neurodegenerative disease that represents the major cause of irreversible blindness. Recent findings have shown which oxidative stress, inflammation, and glutamatergic pathway have main roles in the causes of glaucoma. Lithium is the major commonly used drug for the therapy of chronic mental illness. Lithium therapeutic mechanisms remain complex, including several pathways and gene expression, such as neurotransmitter and receptors, circadian modulation, ion transport, and signal transduction processes. Recent studies have shown that the benefits of lithium extend beyond just the therapy of mood. Neuroprotection against excitotoxicity or brain damages are other actions of lithium. Moreover, recent findings have investigated the role of lithium in glaucoma. The combination of lithium and atypical antipsychotics (AAPs) has been the main common choice for the treatment of bipolar disorder. Due to the possible side effects gradually introduced in therapy. Currently, no studies have focused on the possible actions of AAPs in glaucoma. Recent studies have shown a down regulation of the WNT/ß-catenin pathway in glaucoma, associated with the overactivation of the GSK-3ß signaling. The WNT/ß-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Lithium is correlated with upregulation the WNT/ß-catenin pathway and downregulation of the GSK-3ß activity. Thus, this review focuses on the possible actions of lithium and AAPs, as possible therapeutic strategies, on glaucoma and some of the presumed mechanisms by which these drugs provide their possible benefit properties through the WNT/ß-catenin pathway.

Cannabidiol and the Canonical WNT/ß-Catenin Pathway in Glaucoma.

Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/ß-catenin pathway in glaucoma, associated with overactivation of the GSK-3ß signaling. WNT/ß-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/ß-catenin pathway and decrease of the GSK-3ß activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/ß-catenin pathway. CBD downregulates GSK3-ß activity, an inhibitor of WNT/ß-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/ß-catenin pathway.

Parkinson's Disease: Potential Actions of Lithium by Targeting the WNT/ß-Catenin Pathway, Oxidative Stress, Inflammation and Glutamatergic Pathway.

Parkinson's disease (PD) is one of the major neurodegenerative diseases (ND) which presents a progressive neurodegeneration characterized by loss of dopamine in the substantia nigra pars compacta. It is well known that oxidative stress, inflammation and glutamatergic pathway play key roles in the development of PD. However, therapies remain uncertain and research for new treatment is mandatory. This review focuses on the potential effects of lithium, as a potential therapeutic strategy, on PD and some of the presumed mechanisms by which lithium provides its benefit properties. Lithium medication downregulates GSK-3beta, the main inhibitor of the WNT/ß-catenin pathway. The stimulation of the WNT/ß-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway. Future prospective clinical trials could focus on lithium and its different and multiple interactions in PD.

Lasting and Sex-Dependent Impact of Maternal Immune Activation on Molecular Pathways of the Amygdala.

The prolonged and sex-dependent impact of maternal immune activation (MIA) during gestation on the molecular pathways of the amygdala, a brain region that influences social, emotional, and other behaviors, is only partially understood. To address this gap, we investigated the effects of viral-elicited MIA during gestation on the amygdala transcriptome of pigs, a species of high molecular and developmental homology to humans. Gene expression levels were measured using RNA-Seq on the amygdala for 3-week-old female and male offspring from MIA and control groups. Among the 403 genes that exhibited significant MIA effect, a prevalence of differentially expressed genes annotated to the neuroactive ligand-receptor pathway, glutamatergic functions, neuropeptide systems, and cilium morphogenesis were uncovered. Genes in these categories included corticotropin-releasing hormone receptor 2, glutamate metabotropic receptor 4, glycoprotein hormones, alpha polypeptide, parathyroid hormone 1 receptor, vasointestinal peptide receptor 2, neurotensin, proenkephalin, and gastrin-releasing peptide. These categories and genes have been associated with the MIA-related human neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Gene network reconstruction highlighted differential vulnerability to MIA effects between sexes. Our results advance the understanding necessary for the development of multifactorial therapies targeting immune modulation and neurochemical dysfunction that can ameliorate the effects of MIA on offspring behavior later in life.

Current Status of Drug Targets and Emerging Therapeutic Strategies in the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease affecting the elderly. AD is associated with a progressive decline in memory and cognitive abilities, drastic changes in behavioural patterns and other psychiatric manifestations. It leads to a significant decline in the quality of life at personal, household as well as national level. Although AD was described about hundred years back and multiple theories have been proposed, its exact pathophysiology is unknown. There is no cure for AD and the life expectancy of AD patients remains low at 3-9 years. An accurate understanding of the molecular mechanism(s) involved in the pathogenesis of AD is imperative to devise a successful treatment strategy. This review explains and summarises the current understanding of different therapeutic strategies based on various molecular pathways known to date. Different strategies based on anti-amyloid pathology, glutamatergic pathway, anti-tau, neuroprotection through neurotrophic factors and cholinergic neurotransmission have been discussed. Further, the use of anti-inflammatory drugs, nutraceuticals, and dietary interventions has also been explained in the management of AD. It further describes different pharmacological and dietary interventions being used in treating and/or managing AD. Additionally, this article provides a thorough review of the literature for improving the therapeutic paradigm of AD.

Effect of adolescent androgen manipulation on psychosis-like behaviour in adulthood in BDNF heterozygous and control mice.

RATIONALE: Males are more prone to psychosis, schizophrenia and substance abuse and addiction in adolescence and early adulthood than females. However, the role of androgens during this developmental period is poorly understood. OBJECTIVES: This study aimed to examine how androgens in adolescence influence psychosis-like behaviour in adulthood and whether brain-derived neurotrophic factor (BDNF) is a mediator of these developmental effects. METHODS: Wild-type and BDNF heterozygous male mice were castrated at pre-pubescence and implanted with testosterone or dihydrotestosterone (DHT). In adulthood, we assessed amphetamine- and MK-801-induced hyperlocomotion as a model of psychosis-like behaviour. Western blot analysis was used to quantify levels of the dopamine transporter (DAT) and N-methyl-d-aspartate (NMDA) receptor subunits. RESULTS: While castration itself had little effect on behaviour, adolescent testosterone, but not DHT, significantly reduced amphetamine-induced hyperlocomotion, whereas both testosterone and DHT reduced the effect of MK-801. These effects were similar in mice of either genotype. In wildtype mice, both testosterone and DHT treatment reduced DAT expression in the medial prefrontal cortex (mPFC) but these effects were absent in BDNF heterozygous mice. There were no effects on NMDA receptor subunit levels. CONCLUSIONS: The differential effect of adolescent testosterone and DHT on amphetamine-induced hyperlocomotion in adulthood suggests involvement of conversion of testosterone to estrogen and subsequent modulation of dopaminergic signalling. In contrast, the similar effect of testosterone and DHT treatment on NMDA receptor-mediated hyperlocomotion indicates it is mediated by androgen receptors. The involvement of BDNF in these hormone effects remains to be elucidated. These results demonstrate that, during adolescence, androgens significantly influence key pathways related to various mental illnesses prevalent in adolescence.

NMDA receptors interact with the retrieval memory enhancing effect of pioglitazone in mice.

PURPOSE: The present study has been undertaken to investigate the possible involvement of the glutamatergic pathway in the beneficial effects of pioglitazone on consolidation and retrieval phases of memory. MATERIALS AND METHODS: The Y-maze task was used to assess short-term spatial recognition memory in animals. Scopolamine (1mg/kg, i.p.) or MK-801 (dizocilpine) (0.03, 0.1 and 0.3mg/kg, i.p.) were administered immediately after the training session to impair memory consolidation or 30min before the retention trial to impair memory retrieval. Pioglitazone (10, 20, 40 and 80mg/kg, p.o.) was administered 2h before the retention session in memory retrieval experiments or immediately after the training session in consolidation experiments. And finally NMDA (N-methyl-d-aspartate) (75mg/kg, i.p) was administered 15min before the administration of pioglitazone. RESULTS: 1) MK-801 (0.3mg/kg) impaired the retrieval of spatial recognition memory. 2) Pioglitazone failed to improve MK-801 induced impairment of retrieval of spatial recognition memory. 3) The 20mg/kg dose of pioglitazone significantly improved memory in mice with scopolamine induced impairment of memory retrieval. 4) Sub-effective dose of MK-801 (0.1mg/kg) was capable of reversing the beneficial effect of pioglitazone on retrieval of memory in scopolamine-treated mice, 5) Administration of NMDA (75mg/kg) and a sub-effective dose of pioglitazone (10mg/kg) reversed the effect of scopolamine and promoted memory retrieval. 6) MK-801 did not affect the consolidation phase of spatial recognition memory. 7) Pioglitazone did not affect scopolamine-induced impairment of memory consolidation. CONCLUSIONS: Sub-effective dose of MK-801 is capable of reversing the protective action of pioglitazone on scopolamine-induced impairment of memory retrieval. Additionally, co-administration of 75mg/kg NMDA and a sub-effective dose of pioglitazone potentiated the effect of pioglitazone on memory retrieval impaired by scopolamine. These results support the idea that pioglitazone plays its memory retrieval enhancement role through the glutamatergic pathway.

Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness.

Literature indicates key role of glutamatergic pathway genes in antipsychotic response among schizophrenia patients. However, molecular basis of their underlying role in antipsychotic response remained unexplained. Thus, to unravel their molecular underpinnings, we sought to investigate interactions amongst GRM3, SLC1A1, SLC1A2, SLC1A3, SLC1A4 gene polymorphisms with drug response in south Indian schizophrenia patients. We genotyped 48 SNPs from these genes in 423 schizophrenia patients stratified into low and high severity of illness groups. The SNPs and haplotypic combinations of associated SNPs were examined for their association with antipsychotic response. Multifactor-dimensionality-reduction was further used to explore gene-gene interaction among these SNPs and 53 SNPs from previously studied genes (BDNF, RGS4, SLC6A3, PI4KA, and PIP4K2A). Single SNP and haplotype analyses revealed no significant association with drug response irrespective of severity of illness. Gene-gene interaction analyses yielded promising leads, including an observed synergistic effect between PI4KA_rs165854 and GRM3_rs1468412 polymorphisms and incomplete antipsychotic response in schizophrenia patients with low severity of illness (OR = 12.4; 95%CI = 3.69-41.69). Further, this interaction was also observed in atypical monotherapy (n = 355) and risperidone (n = 260) treatment subgroups (OR = 11.21; 95%CI = 3.30-38.12 and OR = 13.5; 95%CI = 3.03-121.61 respectively). PI4KA is known to be involved in the biosynthesis of phosphatidylinositol-4, 5-bisphosphate which regulates exocytotic fusion of synaptic vesicles (glutamate, dopamine) with the plasma membrane and regulates duration of signal transduction of GPCRs. Whereas GRM3 regulates glutamate and dopamine transmission. Present findings indicate that PI4KA and GRM3 polymorphisms have potential to jointly modulate antipsychotic response. These results warrant additional replication studies to shed further light on these interactions.