Volume 22 Issue 3, March 2019

Geneticists are pushing for ever-greater sample sizes to gain insight into the genetic variation that contributes to psychiatric disorders. Two new genome-wide association studies leverage this approach to provide broad, population-level perspectives on the genetic basis for major depressive disorder and the shared genetic risk that underlies multiple disorders.

Excessive synapse elimination during adolescence and early adulthood has long been hypothesized to underpin the emergence of schizophrenia. A new study reports that induced microglia-like cells derived from schizophrenia patients display increased synapse engulfment, which may be partly mediated by a genetic schizophrenia-risk variant.

Disproportionate reactions to unexpected stimuli and greater attention to perceived threat are cardinal symptoms of post-traumatic stress disorder. Computational psychiatry helps explain how these responses develop and result from abnormalities in learning and prediction during and after traumatic events.

Previous studies have suggested that cortical input can drive spatially tuned responses in hippocampal CA1 neurons. Here we use acute inactivation to demonstrate that CA3 is the predominant driver of CA1 responses under normal conditions.

The authors conducted a genetic meta-analysis of depression and found 269 associated genes. These genes highlight several potential drug repositioning opportunities, and relationships with depression were found for neuroticism and smoking.

Schork et al. identify novel variants contributing to shared risk among psychiatric disorders and suggest that these variants act through the disruption of early neurodevelopment.

An interaction between UTX and 53BP1, which occurs in humans but not mice, promotes neurogenic gene expression that underlies neuronal differentiation and cortical development, perhaps providing insight into human-specific neurodevelopment.

Postmortem studies indicate reduced synaptic density in schizophrenia. Sellgren et al. show increased synaptic pruning in patient-derived cell models and provide evidence that C4 risk variants increase engulfment, while minocycline decreases it.

Shen et al. show that FMRP promotes mitochondrial fusion through HTT. FMRP loss caused fragmented mitochondria and oxidative stress in immature neurons, and enhancing mitochondrial fusion rescued neuronal and behavioral deficits in Fmr1-mutant mice.

The authors report that mitophagy is impaired in Alzheimer’s disease. Stimulation of mitophagy reverses cognitive deficits in nematode and mouse models of Alzheimer’s disease, suggesting a potential therapeutic intervention.

The authors found that white blood cells plug about 2% of capillaries in the brains of Alzheimer’s disease mouse models. When the adhesion of these cells was blocked, cerebral blood flow immediately increased and cognitive performance rapidly improved.

Blood vessels help macrophage entry. Zhou et al. show that activated microvessels serve as critical portals for macrophage entry to boost inflammation after spinal cord injury.

Besnard et al. uncover functional heterogeneity of somatostatin interneurons (SST-INs) in the dorsolateral septum and reveal a role for a subpopulation of SST-INs as hippocampal relays that govern mobility to calibrate adaptive fear responses.

Neuronal responses in a higher-order auditory cortical area reveal striking attention-driven effects, long-term learning, and stimulus–action coupling, indicating a dynamic intermediate stage between sensory and frontal cortex representations.

DeNardo et al. characterize TRAP2, which allows genetic access to neurons based on their activity, and use it to show that neuronal ensembles in prelimbic cortex for remote fear memory undergo dynamic changes during the first 14 days after learning.

PTSD symptom severity in combat veterans was associated with enhanced sensitivity to prediction errors and lower neural tracking of value and learning rate, providing evidence for neurocomputational contributions to trauma-related psychopathology.

van Ede et al. show that both sensory qualities and motor responses associated with information held in mind are accessed simultaneously to guide behavior. The findings help bridge the fields of visual working memory and action planning.

The authors generate 3D brain organoids containing oligodendrocytes, astrocytes, and neurons derived from human pluripotent stem cells. These human oligodendrocytes are transcriptionally similar to primary cells and mature to myelinate axons.

Inhibitory interneurons shape neuronal activity of cortical principal neurons. Yetman et al. developed a genetic strategy to elucidate the organization of inhibitory neuron subtypes sending inputs to principal neurons.