Reaching into the toolbox: Stem cell models to study neuropsychiatric disorders.

Recent advances in genetics, molecular biology, and stem cell biology have accelerated our understanding of neuropsychiatric disorders, like autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). This progress highlights the incredible complexity of both the human brain and mental illnesses from the biochemical to the cellular level. Contributing to the complexity of neuropsychiatric disorders are their polygenic nature, cellular and brain region interconnectivity, and dysregulation of human-specific neurodevelopmental processes. Here, we discuss available tools, including CRISPR-Cas9, and the applications of these tools to develop cell-based two-dimensional (2D) models and 3D brain organoid models that better represent and unravel the intricacies of neuropsychiatric disorder pathophysiology.

Further evidence that pathologic high-frequency oscillations are bursts of population spikes derived from recordings of identified cells in dentate gyrus.

PURPOSE: To analyze activity of identified dentate gyrus granular cells and interneurons during pathologic high-frequency oscillations (pHFOs). METHODS: Pilocarpine-treated epileptic mice were anesthetized with urethane and ketamine. Their heads were fixed in a stereotaxic frame. Extracellular unit activity was recoded with glass micropipettes, whereas multiunit and local field activity was simultaneously recorded with attached tungsten microelectrodes. After electrophysiologic experiments, recorded cells were labeled by neurobiotin and visualized by immunohistochemical methods. KEY FINDINGS AND SIGNIFICANCES: pHFOs containing more than three waves were recorded in our experiments, but pathologic single-population spikes also occurred. Identified granular cells discharged preferentially in synchrony with pHFOs and single population spikes, whereas interneurons decreased their discharge frequency during this time. These experiments provide additional confirmation that pHFOs in the dentate gyrus represent single or recurrent population spikes, which in turn reflect summated hypersynchronous discharges of principal cells.

Plastic changes and disease-modifying effects of scopolamine in the pilocarpine model of epilepsy in rats.

PURPOSE: We describe the use of a clinically relevant pharmacological intervention that alters the clinical history of status epilepticus (SE)-induced spontaneous recurrent seizures (SRS) in the pilocarpine model and the possible plastic changes underlying such an effect. METHODS: Two hours after pilocarpine-induced SE (320-350 mg/kg, i.p.), rats received scopolamine 1-2 mg/kg i.p. or saline, every 6 h for 3 days. After that, osmotic minipumps were implanted for continuous delivery of scopolamine or saline for an additional 14 days. Animals were video-monitored for 12 h/week during the following 3-month period for the occurrence of SRS and, thereafter, were perfused, processed, and coronal brain sections were stained for acetylcholinesterase (AChE) and for the presence of supragranular mossy fibers (Timm). RESULTS: Treatment with scopolamine led to significantly fewer SRS. Staining for AChE in the dentate gyrus was significantly more intense in naïve animals. The scopolamine group had the least intense AChE staining of all groups. However, regression analysis of the AChE staining for this group did not correlate with the presence or absence of SRS, or the latency or frequency of SRS. Supragranular mossy fiber sprouting developed in all animals experiencing pilocarpine-induced SE, irrespective of whether or not they were treated with scopolamine. CONCLUSIONS: Pilocarpine-induced SE in the presence of scopolamine might produce animals that, despite mossy fiber sprouting, were not seen to exhibit spontaneous seizures. In addition, our data suggest that the encountered changes in the AChE staining in the dentate gyrus that followed treatment with scopolamine do not help to explain its disease-modifying effects.