The purpose of this study was to estimate the percentage contribution of genetic and environmental factors to Autism Spectrum Disorder (ASD). Children from Denmark, Finland, Sweden, Israel, and Western Australia who were born between January 1, 1998, and December 31, 2011, were followed up to age 16 years. Data were analyzed from September 23, 2016 through February 4, 2018. The sample consisted of 2,001,631 individuals, of whom 1,027,546 (51.3%) were male. 22,156 subjects were diagnosed with ASD.

Based on population data from these 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences. Maternal effects were minimal and ranged from 0.4% to 1.6%. The results suggest possible modest differences in the sources of ASD risk between countries.

Bai D, Yip BHK, Windham GC, Sourander A, Francis R, Yoffe R, Glasson E, Mahjani B, Suominen A, Leonard H, Gissler M, Buxbaum JD, Wong K, Schendel D, Kodesh A, Breshnahan M, Levine SZ, Parner ET, Hansen SN, Hultman C, Reichenberg A, Sandin S: Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort. JAMA Psychiatry [Epub ahead of print, July 17, 2019; doi: 10.1001/jamapsychiatry.2019.1411 ].

https://www.ncbi.nlm.nih.gov/pubmed/31314057

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Abstract: “Mitochondria vary in morphology and function in different tissues; however, little is known about their molecular diversity among cell types. Here we engineered MitoTag mice, which express a Cre recombinase-dependent green fluorescent protein targeted to the outer mitochondrial membrane, and developed an isolation approach to profile tagged mitochondria from defined cell types. We determined the mitochondrial proteome of the three major cerebellar cell types (Purkinje cells, granule cells and astrocytes) and identified hundreds of mitochondrial proteins that are differentially regulated. Thus, we provide markers of cell-type-specific mitochondria for the healthy and diseased mouse and human central nervous systems, including in amyotrophic lateral sclerosis and Alzheimer’s disease. Based on proteomic predictions, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neuronal mitochondria. We also characterize cell-type differences in mitochondrial calcium buffering via the mitochondrial calcium uniporter (Mcu) and identify regulator of microtubule dynamics protein 3 (Rmdn3) as a determinant of endoplasmic reticulum-mitochondria proximity in Purkinje cells. Our approach enables exploring mitochondrial diversity in many in vivo contexts.”

Fecher C, Trovò L, Müller SA, Snaidero N, Wettmarshausen J, Heink S, Ortiz O, Wagner I, Kühn R, Hartmann J, Karl RM, Konnerth A, Korn T, Wurst W, Merkler D, Lichtenthaler SF, Perocchi F, Misgeld T: Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity. Nature Neurosci. 22(10): 1731-1742 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31501572

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Chronic pain is associated with anxio-depressive comorbidities, but the neuroanatomical substrates remain unknown. A specific serotonergic pathway from the dorsal raphe nucleus to the lateral habenula via the central amygdala is now uncovered as a key neural circuit governing comorbid depressive symptoms in chronic pain.

Specifically, the authors identified a novel pathway involving 5-hydroxytryptamine projections from the dorsal raphe nucleus to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala. The SOM neurons in the amygdala projected directly to the lateral habenula, an area known to be involved in depression. Manipulation of this pathway using pharmacological or optogenetic approaches modulated depression-like behavior in laboratory animals.

Zhou W, Jin Y, Meng Q, Zhu X, Bai T, Tian Y, Mao Y, Wang L, Xie W, Zhong H, Zhang N, Luo MH, Tao W, Wang H, Li J, Li J, Qiu BS, Zhou JN, Li X, Xu H, Wang K, Zhang X, Liu Y, Levin GR, Xu L and Zhang Z: A neural circuit for comorbid depressive symptoms in chronic pain. Nature Neurosci. 22(10): 1649-1658 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31451801

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Patients with brain tumours have a range of symptoms that can vary in severity, from headaches to a decline in cognitive function. The symptoms depend on the tumour type and its size, location and growth rate. Understanding what controls the growth rate of brain tumours might therefore lead to the development of therapies that slow cancer progression and improve the quality of life of people who have this type of cancer. In this report, Venkataramani and colleagues show that cancer cells form excitatory synaptic connections with neurons in the central nervous system. This connection accelerates tumour growth rate and lethality. Specifically, these neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour “microtubes”, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Tumour invasion and growth were reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.

Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, Körber C, Kardorff M, Ratliff M, Xie R, Horstmann H, Messer M, Paik SP, Knabbe J, Sahm F, Kurz FT, Acikgöz AA, Herrmannsdörfer F, Agarwal A, Bergles DE, Chalmers A, Miletic H, Turcan S, Mawrin C, Hänggi D, Liu HK, Wick W, Winkler F, Kuner T: Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573(7775):532-538 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31534219

https://www.ncbi.nlm.nih.gov/pubmed/31534222

https://www.nature.com/articles/d41586-019-02746-7

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Abbreviated Abstract: Adverse childhood experiences are associated with mental and physical health risks that, through biological and psychosocial pathways, likely span generations. Within an individual, telomere length, an established marker of cellular stress and aging, is associated with both adverse childhood experiences and psychopathology, providing the basis for an emerging literature suggesting that telomere length is a biomarker of the health risks linked to early-life adversity both within and across generations. The authors tested the effect of maternal adverse childhood experiences on both the trajectory of infant telomere length and infant social-emotional problems at 18 months of age.

Higher maternal adverse childhood experiences were associated with shorter infant telomere length across infancy and higher infant externalizing behavioral problems at 18 months. In infants whose mothers reported higher scores on the Adverse Childhood Experience questionnaire, greater telomere attrition predicted higher externalizing problems, even when accounting for maternal postnatal depression and prenatal stress. These data demonstrate an interactive pathway between maternal early-life adversity and infant telomere length that predicts emerging behavioral problems in the next generations.

Esteves KC, Jones CW, Wade M, Callerame K, Smith AK, Theall KP and Drury SS: Adverse Childhood Experiences: Implications for Offspring Telomere Length and Psychopathology. Amer. J. Psychiatry [Epub ahead of print, Sept. 6, 2019; doi: 10.1176/appi.ajp.2019.18030335].

https://www.ncbi.nlm.nih.gov/pubmed/31509004

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Insulin resistance in humans is associated with increased risk of major depression. Such a relationship has been also found in rodents fed a high-fat diet. To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, Zemdegs and colleagues tested the effects of metformin, an oral antidiabetic drug, in mice fed a high fat diet. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Metformin also increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. A diet poor in branched-chain amino acids produced similar results. The authors suggest that metformin could be used as add-on therapy to conventional antidepressants to relieve depressive symptoms in patients with metabolic comorbidities.

Zemdegs J, Martin H, Pintana H, Bullich S, Manta S, et al.: Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J. Neurosci. 39(30): 5935-5948 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31160539

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Abstract: “Psychiatric morbidity is high in cities, so identifying potential modifiable urban protective factors is important. We show that exposure to urban green space improves well-being in naturally behaving male and female city dwellers, particularly in districts with higher psychiatric incidence and fewer green resources. Higher green-related affective benefit was related to lower prefrontal activity during negative-emotion processing, which suggests that urban green space exposure may compensate for reduced neural regulatory capacity.”

Tost H, Reichert M, Braun U, Reinhard I, Peters R, Lautenbach S, Hoell A, Schwarz E, Ebner-Priemer U, Zipf A, Meyer-Lindenberg  A: Neural correlates of individual differences in affective benefit of real-life urban green space exposure. Nature Neuroscience 22(9): 1389-1393 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31358990

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Abstract: “β-amyloid (Aβ)-dependent neuronal hyperactivity is believed to contribute to the circuit dysfunction that characterizes the early stages of Alzheimer’s disease (AD). Although experimental evidence in support of this hypothesis continues to accrue, the underlying pathological mechanisms are not well understood. In this experiment, we used mouse models of Aβ-amyloidosis to show that hyperactivation is initiated by the suppression of glutamate reuptake. Hyperactivity occurred in neurons with preexisting baseline activity, whereas inactive neurons were generally resistant to Aβ-mediated hyperactivation. Aβ-containing AD brain extracts and purified Aβ dimers were able to sustain this vicious cycle. Our findings suggest a cellular mechanism of Aβ-dependent neuronal dysfunction that can be active before plaque formation.”

Zott B et al.: A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science 365 (6453): 559-565 (2019).

and

Selkoe DJ: Early network dysfunction in Alzheimer’s disease. Science 365 (6453): 540-541 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31395769

https://www.ncbi.nlm.nih.gov/pubmed/31395777

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Abbreviated Abstract: “Aging drives a progressive decline in cognition and decreases synapse numbers and synaptic function in the brain, thereby increasing the risk for neurodegenerative disease. Pioneering studies showed that introduction of blood from young mice into aged mice reversed age-associated cognitive impairments and increased synaptic connectivity in brain, suggesting that young blood contains specific factors that remediate age-associated decreases in brain function. However, whether such factors in blood from young animals act directly on neurons to enhance synaptic connectivity, or whether they act by an indirect mechanism remains unknown. Moreover, which factors in young blood mediate cognitive improvements in old mice is incompletely understood. “

Here, the authors show that serum extracted from the blood of young but not old mice, directly increased dendritic arborization, augmented synapse numbers and elevated synaptic N-methyl-d-aspartate (NMDA) receptors. They suggest that thrombospondin-4 (THBS4) and SPARC-like protein 1 (SPARCL1) are mediators of this effect. Both proteins were enriched in serum from young mice. Recombinant THBS4 and SPARCL1 both increased dendritic arborization and doubled synapse numbers in cultured neurons. In addition, SPARCL1 but not THBS4 tripled NMDA receptor-mediated synaptic responses. The study concluded that at least two proteins enriched in young blood, THBS4 and SPARCL1, directly act on neurons as synaptogenic factors. These proteins may represent rejuvenation factors that enhance synaptic connectivity by increasing dendritic arborization, synapse formation, and synaptic transmission.

Gan KJ and Südhof TC: Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proc. Natl. Acad. Sci USA 116(25):12524-12533 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31160442

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Abstract: “Science fiction notions of altering problematic memories are starting to become reality as techniques emerge through which unique memories can be edited. Here we review memory-editing research with a focus on improving the treatment of psychopathology. Studies highlight two windows of memory vulnerability: initial storage, or consolidation; and re-storage after retrieval, or reconsolidation. Techniques have been identified that can modify memories at each stage, but translating these methods from animal models to humans has been challenging and implementation into clinical therapies has produced inconsistent benefits. The science of memory editing is more complicated and nuanced than fiction, but its rapid development holds promise for future applications.”

Phelps EA and Hofmann SG: Memory editing from science fiction to clinical practice. Nature 572(7767): 43-40 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31367027

https://www.nature.com/articles/s41586-019-1433-7.pdf

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