SUMMARYPurpose: To analyze activity of identified dentate gyrus granular cells and interneurons during pathologic highfrequency 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.

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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 cellbased two-dimensional (2D) models and 3D brain organoid models that better represent and unravel the intricacies of neuropsychiatric disorder pathophysiology.

Goal_of this manuscript is to investigate whether changes that exist in epileptic brain generating spontaneous seizures are reflected in the pattern of the Up-Down state recorded from the neocortex and dentate gyrus. Experiments were carried out on naive and epileptic mice under urethane anesthesia. Local field potentials were recorded with chronically implanted microelectrodes and single unit activity was recorded with glass microelectrodes. Recorded neurons were labeled by neurobiotine and identified later as granular cells or interneurons in histological sections. The following major features differentiate the pattern of Up-Down State in epilepsy from normal. 1) The duration of Up and Down phases is significantly longer. 2) Recovery of network excitability after termination of the Up phase is longer. 3) UP-spikes occur during the Up phase, which transiently interrupt the development of the normal electrographic pattern of Up phase. Our data provide evidence that UP-spikes result from gigantic EPSPs generated in response to afferent activity. UP-spikes in the neocortex and dentate gyrus occur in close temporal relationship indicating the existence of direct or indirect pathological functional connections between these areas. Changes in the duration of UP- and Down phases as well increased time of recovery of excitability of epileptic brain after termination of Up phase suggest alterations in the homeostatic properties of neuronal network in epileptic brain. We suggest that the existence of UP-spikes in epileptic brain may be an additional electrographic pattern indicating epileptogenicity. Unraveling the neuronal substrates of UP-spikes may further improve our understanding of the mechanisms of epilepsy.

Summary: 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.