Estradiol regulates voltage-gated potassium currents in corticotropin-releasing hormone neurons.

Corticotropin-releasing hormone (CRH) neurons are the primary neural population controlling the hypothalamic-pituitary-adrenal (HPA) axis and the secretion of adrenal stress hormones. Previous work has demonstrated that stress hormone secretion can be regulated by circulating levels of estradiol. However, the effect of estradiol on CRH neuron excitability is less clear. Here, we show that chronic estradiol replacement following ovariectomy increases two types of potassium channel currents in CRH neurons: fast inactivating voltage-gated A-type K+ channel currents (IA) and non-inactivating M-type K+ channel currents (IM). Despite the increase in K+ currents following estradiol replacement, there was no overall change in CRH neuron spiking excitability assessed with either frequency-current curves or current ramps. Together, these data reveal a complex picture whereby ovariectomy and estradiol replacement differentially modulate distinct aspects of CRH neuron and HPA axis function.

Intelligence quotient decline following frequent or dependent cannabis use in youth: a systematic review and meta-analysis of longitudinal studies.

Previous systematic reviews and meta-analyses of cross-sectional data assessing the effect of cannabis on cognitive functioning and intelligence show inconsistent results. We hypothesized that frequent and dependent cannabis use in youth would be associated with Intelligence Quotient (IQ) decline. This study is a systematic review and meta-analysis. We searched Embase, PubMed and PsychInfo from inception to 24 January 2020. We included studies with non-treatment seeking samples and pre- and post-exposure measures of IQ. We requested data from authors if summary data was not available from published work. We preregistered our review with PROSPERO (ID no. CRD42019125624). We found seven cohort studies including 808 cases and 5308 controls. We found a significant effect for the association between frequent or dependent cannabis use in youth and IQ change, Cohen's d = -0.132 (95% CI -0.198 to -0.066) p < 0.001. Statistical heterogeneity between studies was also low at I2 = 0.2%. Study quality was moderate to high. This translates to an average decline of approximately 2 IQ points following exposure to cannabis in youth. Future studies should have longer periods of follow up to assess the magnitude of developmental impact.

Prolonged Type 1 Metabotropic Glutamate Receptor Dependent Synaptic Signaling Contributes to Spino-Cerebellar Ataxia Type 1.

UNLABELLED: Type 1 metabotropic glutamate receptor (mGluR1)-dependent signaling at parallel fiber to Purkinje neuron synapses is critical for cerebellar function. In a mouse model of human spino-cerebellar ataxia type 1 (early SCA1, 12 weeks) we find prolonged parallel fiber mGluR1-dependent synaptic currents and calcium signaling. Acute treatment with a low dose of the potent and specific activity-dependent mGluR1-negative allosteric modulator JNJ16259685 shortened the prolonged mGluR1 currents and rescued the moderate ataxia. Our results provide exciting new momentum for developing mGluR1-based pharmacology to treat ataxia. SIGNIFICANCE STATEMENT: Ataxia is a progressive and devastating degenerative movement disorder commonly associated with loss of cerebellar function and with no known cure. In the early stages of a mouse model of human spinocerebellar ataxia type 1, SCA1, where mice exhibit only moderate motor impairment, we detect excess "gain of function" of metabotropic glutamate receptor signaling at an important cerebellar synapse. Because careful control of this type of signaling is critical for cerebellar function in mice and humans, we sought to remove the excess signaling with a powerful, readily available pharmacological modulator. Remarkably, this pharmacological treatment acutely restored normal motor function in the ataxic mice. Our results pave the way for exploring a new avenue for early treatment of human ataxias.

Are Type 1 metabotropic glutamate receptors a viable therapeutic target for the treatment of cerebellar ataxia?

The cerebellum is a key brain structure for accurate coordination of sensory and motor function. Compared with other brain regions, the cerebellum expresses a particularly high level of Type 1 metabotropic glutamate receptors (mGluR1). In this review we aim to explore the significance of these receptors for cerebellar synapse function and their potential for treating cerebellar ataxia, a poorly treated degenerative motor disorder that is often hereditary. We find a significant and historical literature showing pivotal mechanisms linking mGluR1 activity with healthy cerebellar synaptic function and motor coordination. This is best illustrated by the impaired motor behaviour in mGluR1 knockout mice that bears strong resemblance to human ataxias. More recent literature also indicates that an imbalance of mGluR1 signalling is as critical as its removal. Too much, as well as too little, mGluR1 activity contributes to ataxia in several clinically relevant mouse models, and perhaps also in humans. Given the availability and ongoing refinement of selective pharmacological tools to either reduce (negative allosteric modulation) or boost (positive allosteric modulation) mGluR1 activity, our findings suggest that pharmacological manipulation of these receptors should be explored as an exciting new approach for the treatment of a variety of human cerebellar ataxias.

Transient reversal of the sodium/calcium exchanger boosts presynaptic calcium and synaptic transmission at a cerebellar synapse.

The sodium/calcium exchanger (NCX) is a widespread transporter that exchanges sodium and calcium ions across excitable membranes. Normally, NCX mainly operates in its "forward" mode, harnessing the electrochemical gradient of sodium ions to expel calcium. During membrane depolarization or elevated internal sodium levels, NCX can instead switch the direction of net flux to expel sodium and allow calcium entry. Such "reverse"-mode NCX operation is frequently implicated during pathological or artificially extended periods of depolarization, not during normal activity. We have used fast calcium imaging, mathematical simulation, and whole cell electrophysiology to study the role of NCX at the parallel fiber-to-Purkinje neuron synapse in the mouse cerebellum. We show that nontraditional, reverse-mode NCX activity boosts the amplitude and duration of parallel fiber calcium transients during short bursts of high-frequency action potentials typical of their behavior in vivo. Simulations, supported by experimental manipulations, showed that accumulation of intracellular sodium drove NCX into reverse mode. This mechanism fueled additional calcium influx into the parallel fibers that promoted synaptic transmission to Purkinje neurons for up to 400 ms after the burst. Thus we provide the first functional demonstration of transient and fast NCX-mediated calcium entry at a major central synapse. This unexpected contribution from reverse-mode NCX appears critical for shaping presynaptic calcium dynamics and transiently boosting synaptic transmission, and is likely to optimize the accuracy of cerebellar information transfer.

Climate change and mental health: time for action and advocacy.

Climate change poses an existential threat to our planet and our health. We explore the intersections of climate change and mental health which has been under-recognised to date. Climate change can affect mental health directly through the effects of extreme weather events such as heat, drought and flooding, and indirectly through increasing rates of migration and inequality. Vulnerable individuals with neuropsychiatric disorders will be particularly at risk. Emerging evidence is also showing effects of air pollution on brain development. Mitigation efforts related to reducing carbon emissions will have both direct and indirect effects on mental health. A further consideration demonstrated by the COVID-19 pandemic is that the spread of infectious disease can have substantial effects on the mental health of the population. With climate change and biodiversity loss, pandemics could recur in the future with increasing frequency. It is now essential that mental health professionals be equipped as agents for climate action.

Plasticity of intrinsic excitability across the estrous cycle in hypothalamic CRH neurons.

Stress responses are highly plastic and vary across physiological states. The female estrous cycle is associated with a number of physiological changes including changes in stress responses, however, the mechanisms driving these changes are poorly understood. Corticotropin-releasing hormone (CRH) neurons are the primary neural population controlling the hypothalamic-pituitary-adrenal (HPA) axis and stress-evoked corticosterone secretion. Here we show that CRH neuron intrinsic excitability is regulated over the estrous cycle with a peak in proestrus and a nadir in estrus. Fast inactivating voltage-gated potassium channel (IA) currents showed the opposite relationship, with current density being lowest in proestrus compared to other cycle stages. Blocking IA currents equalized excitability across cycle stages revealing a role for IA in mediating plasticity in stress circuit function over the female estrous cycle.

Motor and Cerebellar Architectural Abnormalities during the Early Progression of Ataxia in a Mouse Model of SCA1 and How Early Prevention Leads to a Better Outcome Later in Life.

Exposing developing cerebellar Purkinje neurons (PNs) to mutant Ataxin1 (ATXN1) in 82Q spinocerebellar ataxia type 1 (SCA1) mice disrupts motor behavior and cerebellar climbing fiber (CF) architecture from as early as 4 weeks of age. In contrast, if mutant ATXN1 expression is silenced until after cerebellar development is complete, then its impact on motor behavior and cerebellar architecture is greatly reduced. Under these conditions even 6 month old SCA1 mice exhibit largely intact motor behavior and molecular layer (ML) and CF architecture but show a modest reduction in PN soma area as a first sign of cerebellar disruption. Our results contrast the sensitivity of the developing cerebellum and remarkable resilience of the adult cerebellum to mutant ATXN1 and imply that SCA1 in this mouse model is both a developmental and neurodegenerative disorder.

Functional Connectivity Anomalies in Adolescents with Psychotic Symptoms.

BACKGROUND: Previous magnetic resonance imaging (MRI) research suggests that, prior to the onset of psychosis, high risk youths already exhibit brain abnormalities similar to those present in patients with schizophrenia. OBJECTIVES: The goal of the present study was to describe the functional organization of endogenous activation in young adolescents who report auditory verbal hallucinations (AVH) in view of the "distributed network" hypothesis of psychosis. We recruited 20 young people aged 13-16 years who reported AVHs and 20 healthy controls matched for age, gender and handedness from local schools. METHODS: Each participant underwent a semi-structured clinical interview and a resting state (RS) neuroimaging protocol. We explored functional connectivity (FC) involving three different networks: 1) default mode network (DMN) 2) salience network (SN) and 3) central executive network (CEN). In line with previous findings on the role of the auditory cortex in AVHs as reported by young adolescents, we also investigated FC anomalies involving both the primary and secondary auditory cortices (A1 and A2, respectively). Further, we explored between-group inter-hemispheric FC differences (laterality) for both A1 and A2. Compared to the healthy control group, the AVH group exhibited FC differences in all three networks investigated. Moreover, FC anomalies were found in a neural network including both A1 and A2. The laterality analysis revealed no between-group, inter-hemispheric differences. CONCLUSIONS: The present study suggests that young adolescents with subclinical psychotic symptoms exhibit functional connectivity anomalies directly and indirectly involving the DMN, SN, CEN and also a neural network including both primary and secondary auditory cortical regions.

Nonsuicidal self-injury, suicidal thoughts and suicide attempts among sexual minority youth in Ireland during their emerging adult years.

AIM: This study aimed to examine whether or not sexual minority youth constitute an at-risk group for nonsuicidal self-injury, suicidal ideation or suicide attempts during their emerging adult years. METHODS: Using data from the Challenging Times Study, a population-based study of psychopathology and suicide in Ireland, analyses were conducted to test the associations between sexual minority status and the odds of any lifetime experience of nonsuicidal self-injury, suicidal thoughts or suicide attempts among Irish youth aged 19-24 years. RESULTS: Sexual minority youth had 6.6-fold (95% CI 1.7-24.7) increased risk of nonsuicidal self-injury, a 5.0-fold (95% CI 1.3-18.3) increased risk of suicidal ideation, a 7.7-fold (95% CI 1.8-32.0) increased risk of suicide intent and a 6.8-fold (95% CI 1.6-27.6) increased risk of a suicide attempt during their lifetime compared to their heterosexual peers. CONCLUSIONS: This study shows that emerging adulthood is a period of risk for suicide and nonsuicidal self-injurious behaviour among sexual minority youth.

Psychotic experiences in the population: Association with functioning and mental distress.

Psychotic experiences are far more common in the population than psychotic disorder. They are associated with a number of adverse outcomes but there has been little research on associations with functioning and distress. We wished to investigate functioning and distress in a community sample of adolescents with psychotic experiences. Two hundred and twelve school-going adolescents were assessed for psychotic experiences, mental distress associated with these experiences, global (social/occupational) functioning on the Children's Global Assessment Scale, and a number of candidate mediator variables, including psychopathology, suicidality, trauma (physical and sexual abuse and exposure to domestic violence) and neurocognitive functioning. Seventy five percent of participants who reported psychotic experiences reported that they found these experiences distressing (mean score for severity of distress was 6.9 out of maximum 10). Participants who reported psychotic experiences had poorer functioning than participants who did not report psychotic experiences (respective means: 68.6, 81.9; OR=0.25, 95% CI=0.14-0.44). Similarly, participants with an Axis-1 psychiatric disorder who reported psychotic experiences had poorer functioning than participants with a disorder who did not report psychotic experiences (respective means: 61.8, 74.5; OR=0.28, 95% CI=0.12-0.63). Candidate mediator variables explained some but not all of the relationship between psychotic experiences and functioning (OR=0.48, 95% CI=0.22-1.05, P<0.07). Young people with psychotic experiences have poorer global functioning than those who do not, even when compared with other young people with psychopathology (but who do not report psychotic experiences). A disclosure of psychotic experiences should alert treating clinicians that the individual may have significantly more functional disability than suggested by the psychopathological diagnosis alone.

Functional contributions of glutamate transporters at the parallel fibre to Purkinje neuron synapse-relevance for the progression of cerebellar ataxia.

BACKGROUND: Rapid uptake of glutamate by neuronal and glial glutamate transporters (EAATs, a family of excitatory amino acid transporters) is critical for shaping synaptic responses and for preventing excitotoxicity. Two of these transporters, EAAT4 in Purkinje neurons (PN) and EAAT1 in Bergmann glia are both enriched within the cerebellum and altered in a variety of human ataxias. RESULTS: PN excitatory synaptic responses and firing behaviour following high frequency parallel fibre (PF) activity commonly encountered during sensory stimulation in vivo were adversely influenced by acute inhibition of glutamate transporters. In the presence of a non-transportable blocker of glutamate transporters we observed very large amplitude and duration excitatory postsynaptic currents accompanied by excessive firing of the PNs. A combination of AMPA and mGluR1, but not NMDA, type glutamate receptor activation powered the hyper-excitable PN state. The enhanced PN excitability also recruited a presynaptic mGluR4 dependent mechanism that modified short term plasticity at the PF synapse. CONCLUSIONS: Our findings indicate that reduced glutamate transporter activity, as occurs in the early stages of some forms of human cerebellar ataxias, excessively excites PNs and disrupts the timing of their output. Our findings raise the possibility that sustaining cerebellar glutamate uptake may provide a therapeutic approach to prevent this disruption and the glutamate excitotoxicity-induced PN death that signals the end point of the disease.

Developmentally regulated expression of Sox9 and microRNAs 124, 128 and 23 in neuroepithelial stem cells in the developing spinal cord.

Central nervous system development is a complex process involving many interacting factors. MicroRNAs have recently been identified as playing key intrinsic roles in development however few of their specific targets have been identified in vivo. The transcription factor Sox9 has recently been identified as a target of miR-124 in the adult mouse sub-ventricular zone. Here we investigate the expression of the microRNAs miR-124, miR-128 and miR-23 and that of transcription factor Sox9, in neuroepithelial stem cells in the developing spinal cord. Furthermore we investigate if neurogenesis in embryonic neuroepithelial cells in the spinal cord might also be regulated by the interaction of Sox9 and miR-124. We provide evidence of the spatial and temporal regulation of miR-124, miR-128, miR-23 and Sox9, and taken together with recent findings we provide evidence that Sox9 may also be target of miR-124 in developing spinal cord neuroepithelial cells.