Molecular mechanisms of schizophrenia: Insights from human genetics.

Schizophrenia is a debilitating psychiatric disorder that affects millions of people worldwide; however, its etiology is poorly understood at the molecular and neurobiological levels. A particularly important advance in recent years is the discovery of rare genetic variants associated with a greatly increased risk of developing schizophrenia. These primarily loss-of-function variants are found in genes that overlap with those implicated by common variants and are involved in the regulation of glutamate signaling, synaptic function, DNA transcription, and chromatin remodeling.

Deep proteomics identifies shared molecular pathway alterations in synapses of patients with schizophrenia and bipolar disorder and mouse model.

Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We use quantitative mass spectrometry to carry out deep, unbiased proteomic profiling of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared with controls, SCZ and BP synapses show substantial and similar proteomic alterations.

NMDA receptor-dependent prostaglandin-endoperoxide synthase 2 induction in neurons promotes glial proliferation during brain development and injury.

Astrocytes play critical roles in brain development and disease, but the mechanisms that regulate astrocyte proliferation are poorly understood. We report that astrocyte proliferation is bi-directionally regulated by neuronal activity via NMDA receptor (NMDAR) signaling in neurons. Prolonged treatment with an NMDAR antagonist reduced expression of cell-cycle-related genes in astrocytes in hippocampal cultures and suppressed astrocyte proliferation in vitro and in vivo, whereas neuronal activation promoted astrocyte proliferation, dependent on neuronal NMDARs.