Molecular evidence of altered stress responsivity related to neuroinflammation in the schizophrenia midbrain.

Stress and inflammation are risk factors for schizophrenia. Chronic psychosocial stress is associated with subcortical hyperdopaminergia, a core feature of schizophrenia. Hyperdopaminergia arises from midbrain neurons, leading us to hypothesise that changes in stress response pathways may occur in this region.

Maternal immune activation and estrogen receptor modulation induce sex-specific dopamine-related behavioural and molecular alterations in adult rat offspring.

Dopamine dysregulation contributes to psychosis and cognitive deficits in schizophrenia that can be modelled in rodents by inducing maternal immune activation (MIA). The selective estrogen receptor (ER) modulator, raloxifene, can improve psychosis and cognition in men and women with schizophrenia. However, few studies have examined how raloxifene may exert its therapeutic effects in mammalian brain in both sexes during young adulthood (age relevant to most prevalent age at diagnosis).

GRIN2B gene expression is increased in the anterior cingulate cortex in major depression.

The glutamatergic system may be central to the neurobiology and treatment of major depressive disorder (MDD) and psychosis. Despite the success of N-methyl-D-aspartate receptor (NMDAR) antagonists for the treatment of MDD, little is known regarding the expression of these glutamate receptors in MDD. In this study we measured gene expression, via qRT-PCR, of the major NMDAR subunits, in the anterior cingulate cortex (ACC) in MDD subjects with and without psychosis, and non-psychiatric controls.

The Role of the Microbiome in the Metabolic Health of People with Schizophrenia and Related Psychoses: Cross-Sectional and Pre-Post Lifestyle Intervention Analyses.

The microbiome has been implicated in the development of metabolic conditions which occur at high rates in people with schizophrenia and related psychoses. This exploratory proof-of-concept study aimed to: (i) characterize the gut microbiota in antipsychotic naïve or quasi-naïve people with first-episode psychosis, and people with established schizophrenia receiving clozapine therapy; (ii) test for microbiome changes following a lifestyle intervention which included diet and exercise education and physical activity. Participants were recruited from the Eastern Suburbs Mental Health Service, Sydney, Australia.

Inflammation-related transcripts define "high" and "low" subgroups of individuals with schizophrenia and bipolar disorder in the midbrain.

Dopamine dysregulation in schizophrenia may be associated with midbrain inflammation. Previously, we found elevated levels of pro-inflammatory cytokine mRNAs in the post-mortem midbrain of people with schizophrenia (46%) but not from unaffected controls (0%) using a brain cohort from Sydney, Australia. Here, we measured cytokine mRNAs and proteins in the midbrain in the Stanley Medical Research Institute (SMRI) array cohort (N = 105).

Alterations in the kynurenine pathway and excitatory amino acid transporter-2 in depression with and without psychosis: Evidence of a potential astrocyte pathology.

Evidence, largely obtained from peripheral studies, suggests that alterations in the kynurenine pathway contribute to the aetiology of depression and disorders involving psychosis. Stimulation of the kynurenine pathway leads to the formation of neuroactive metabolites, including kynurenic acid (predominantly in astrocytes) and quinolinic acid (predominantly in microglia), which are antagonists and agonists of the glutamate NMDA receptor, respectively. In this study, we measured gene expression via qRT-PCR of the main kynurenine pathway enzymes in the anterior cingulate cortex (ACC) in people with major depressive disorder and matched controls.

N-Methyl-d-Aspartate receptor and inflammation in dorsolateral prefrontal cortex in schizophrenia.

Lower N-methyl-d-aspartate receptor (NMDAR) GluN1 subunit levels and heightened neuroinflammation are found in the cortex in schizophrenia. Since neuroinflammation can lead to changes in NMDAR function, it is possible that these observations are linked in schizophrenia. We aimed to extend our previous studies by measuring molecular indices of NMDARs that define key functional properties of this receptor - particularly the ratio of GluN2A and GluN2B subunits - in dorsolateral prefrontal cortex (DLPFC) from schizophrenia and control cases (37/37).

Reductions in midbrain GABAergic and dopamine neuron markers are linked in schizophrenia.

Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes.

Effect of Immune Activation during Early Gestation or Late Gestation on Inhibitory Markers in Adult Male Rats.

People with schizophrenia exhibit deficits in inhibitory neurons and cognition. The timing of maternal immune activation (MIA) may present distinct schizophrenia-like phenotypes in progeny. We investigated whether early gestation [gestational day (GD) 10] or late gestation (GD19) MIA, via viral mimetic polyI:C, produces deficits in inhibitory neuron indices (GAD1, PVALB, SST, SSTR2 mRNAs) within cortical, striatal, and hippocampal subregions of male adult rat offspring.

Evidence for enhanced androgen action in the prefrontal cortex of people with bipolar disorder but not schizophrenia or major depressive disorder.

Anxiety and depressive disorders are more prevalent in hypogonadal men. Low testosterone levels are associated with greater negative symptoms and impaired cognition in men with schizophrenia. Thus, androgens may contribute to brain pathophysiology in psychiatric disorders.

Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation.

The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence the functional properties of midbrain dopamine neurons, midbrain inflammation may play a role in schizophrenia by contributing to presynaptic dopamine abnormalities. Thus, we quantified inflammatory markers in dopaminergic areas of the midbrain of people with schizophrenia and matched controls.

Considerations for optimal use of postmortem human brains for molecular psychiatry: lessons from schizophrenia.

Schizophrenia is a disabling disease impacting millions of people around the world, for which there is no known cure. Current antipsychotic treatments for schizophrenia mainly target psychotic symptoms, do little to ameliorate social or cognitive deficits, have side-effects that cause weight gain, and diabetes and 30% of people do not respond. Thus, better therapeutics for schizophrenia aimed at the route biologic changes are needed and discovering the underlying neurobiology is key to this quest.

Effects of Immune Activation during Early or Late Gestation on -Methyl-d-Aspartate Receptor Measures in Adult Rat Offspring.

Background: Glutamatergic receptor [-methyl-d-aspartate receptor (NMDAR)] alterations within cortex, hippocampus, and striatum are linked to schizophrenia pathology. Maternal immune activation (MIA) is an environmental risk factor for the development of schizophrenia in offspring. In rodents, gestational timing of MIA may result in distinct behavioral outcomes in adulthood, but how timing of MIA may impact the nature and extent of NMDAR-related changes in brain is not known.

Adolescent testosterone influences BDNF and TrkB mRNA and neurotrophin-interneuron marker relationships in mammalian frontal cortex.

Late adolescence in males is a period of increased susceptibility for the onset of schizophrenia, coinciding with increased circulating testosterone. The cognitive deficits prevalent in schizophrenia may be related to unhealthy cortical interneurons, which are trophically dependent on brain derived neurotrophic factor. We investigated, under conditions of depleted (monkey and rat) and replaced (rat) testosterone over adolescence, changes in gene expression of cortical BDNF and TrkB transcripts and interneuron markers and the relationships between these mRNAs and circulating testosterone.

The effect of adolescent testosterone on hippocampal BDNF and TrkB mRNA expression: relationship with cell proliferation.

Background: Testosterone attenuates postnatal hippocampal neurogenesis in adolescent male rhesus macaques through altering neuronal survival. While brain-derived neurotropic factor (BDNF)/ tyrosine kinase receptor B (TrkB) are critical in regulating neuronal survival, it is not known if the molecular mechanism underlying testosterone's action on postnatal neurogenesis involves changes in BDNF/TrkB levels. First, (1) we sought to localize the site of synthesis of the full length and truncated TrkB receptor in the neurogenic regions of the adolescent rhesus macaque hippocampus.

Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: amelioration by COX-2 inhibition.

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence.

Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects.

Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain.

Rationale: Adolescence is a developmental period of complex neurobiological change and heightened vulnerability to psychiatric illness. As a result, understanding factors such as sex and stress hormones which drive brain changes in adolescence, and how these factors may influence key neurotransmitter systems implicated in psychiatric illness, is paramount.

Objectives: In this review, we outline the impact of sex and stress hormones at adolescence on dopamine neurotransmission, a signaling pathway which is critical to healthy brain function and has been implicated in psychiatric illness.

Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra.

Background: Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17β-estradiol and activation of estrogen receptors (ER).