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Despite an abundance of pharmacologic and surgical epilepsy treatments, there remain millions of patients suffering from poorly controlled seizures. One approach to closing this treatment gap may be found through a deeper mechanistic understanding of the network alterations that underly this aberrant activity. Functional optical imaging in vertebrate models provides powerful advantages to this end, enabling the spatiotemporal acquisition of individual neuron activity patterns across multiple seizures. This coupled with the advent of genetically encoded indicators, be them for specific ions, neurotransmitters or voltage, grants researchers unparalleled access to the intact nervous system. Here, we will review how in vivo functional optical imaging in various vertebrate seizure models has advanced our knowledge of seizure dynamics, principally seizure initiation, propagation and termination. [ABSTRACT FROM AUTHOR]

Significance: Intravital cellular calcium imaging has emerged as a powerful tool to investigate how different types of neurons interact at the microcircuit level to produce seizure activity, with newfound potential to understand epilepsy. Although many methods exist to measure seizure-related activity in traditional electrophysiology, few yet exist for calcium imaging. Aim: To demonstrate an automated algorithmic framework to detect seizure-related events using calcium imaging--including the detection of pre-ictal spike events, propagation of the seizure wavefront, and terminal spreading waves for both population- level activity and that of individual cells. Approach: We developed an algorithm for precise recruitment detection of population and individual cells during seizure-associated events, which broadly leverages averaged population activity and high-magnitude slope features to detect single-cell pre-ictal spike and seizure recruitment. We applied this method to data recorded using awake in vivo two-photon calcium imaging during pentylenetetrazol-induced seizures in mice. Results: We demonstrate that our detected recruitment times are concordant with visually identified labels provided by an expert reviewer and are sufficiently accurate to model the spatiotemporal progression of seizure-associated traveling waves. Conclusions: Our algorithm enables accurate cell recruitment detection and will serve as a useful tool for researchers investigating seizure dynamics using calcium imaging. [ABSTRACT FROM AUTHOR]

The Ca2+ hypothesis for Alzheimer's disease (AD) conceives Ca2+ dyshomeostasis as a common mechanism of AD; the cause of Ca2+ dysregulation, however, is obscure. Meanwhile, hyperactivities of N‐Methyl‐D‐aspartate receptors (NMDARs), the primary mediator of Ca2+ influx, are reported in AD. GluN3A (NR3A) is an NMDAR inhibitory subunit. We hypothesize that GluN3A is critical for sustained Ca2+ homeostasis and its deficiency is pathogenic for AD. Cellular, molecular, and functional changes were examined in adult/aging GluN3A knockout (KO) mice. The GluN3A KO mouse brain displayed age‐dependent moderate but persistent neuronal hyperactivity, elevated intracellular Ca2+, neuroinflammation, impaired synaptic integrity/plasticity, and neuronal loss. GluN3A KO mice developed olfactory dysfunction followed by psychological/cognitive deficits prior to amyloid‐β/tau pathology. Memantine at preclinical stage prevented/attenuated AD syndromes. AD patients' brains show reduced GluN3A expression. We propose that chronic "degenerative excitotoxicity" leads to sporadic AD, while GluN3A represents a primary pathogenic factor, an early biomarker, and an amyloid‐independent therapeutic target. [ABSTRACT FROM AUTHOR]

The medial septum (MS) is a potential target for modulating hippocampal activity. However, given the multiple cell types involved, the changes in hippocampal neural activity induced by MS stimulation have not yet been fully characterized. We combined MS optogenetic stimulation with local field potential (LFP) recordings from the hippocampus and leveraged machine learning techniques to explore how activating or inhibiting multiple MS neuronal subpopulations using different optical stimulation parameters affects hippocampal LFP biomarkers. First, of the seven different optogenetic viral vectors used for modulating different neuronal subpopulations, only two induced a substantial change in hippocampal LFP. Second, we found hippocampal low-gamma band to be most effectively modulated by the stimulation. Third, the hippocampal biomarkers were sensitive to the optogenetic virus type and the stimulation frequency, establishing those parameters as the critical ones for the regulation of hippocampal biomarker activity. Last, we built a Gaussian process regression model to describe the relationship between stimulation parameters and activity of the biomarker as well as to identify the optimal parameters for biomarker modulation. This new machine learning approach can further our understanding of the effects of neural stimulation and guide the selection of optimal parameters for neural control. [ABSTRACT FROM AUTHOR]

Cell transplantation therapy provides a regenerative strategy for neural repair. We tested the hypothesis that selective excitation of transplanted induced pluripotent stem cell-derived neural progenitor cells (iPS-NPCs) could recapitulate an activity-enriched microenvironment that confers regenerative benefits for the treatment of stroke. Mouse iPS-NPCs were transduced with a novel optochemogenetics fusion protein, luminopsin 3 (LM03), which consisted of a bioluminescent luciferase, Gaussia luciferase, and an opsin, Volvox Channelrhodopsin 1. These LM03-iPS-NPCs can be activated by either photostimulation using light or by the luciferase substrate coelenterazine (CTZ). In vitro stimulations of LM03-iPS-NPCs increased expression of synapsin-1, postsynaptic density 95, brain derived neurotrophic factor (BDNF), and stromal cell-derived factor 1 and promoted neurite outgrowth. After transplantation into the ischemic cortex of mice, LM03-iPS-NPCs differentiated into mature neurons. Synapse formation between implanted and host neurons was identified using immunogold electron microscopy and patch-clamp recordings. Stimulation of transplanted cells with daily intranasal administration of CTZ enhanced axonal myelination, synaptic transmission, improved thalamocortical connectivity, and functional recovery. Patch-clamp and multielectrode array recordings in brain slices showed that CTZ or light stimulation facilitated synaptic transmission and induced neuroplasticity mimicking the LTP of EPSPs. Stroke mice received the combined LM03-iPS-NPC/CTZ treatment, but not cell or CTZ alone, showed enhanced neural network connections in the peri-infarct region, promoted optimal functional recoveries after stroke in male and female, young and aged mice. Thus, excitation of transplanted cells via the noninvasive optochemogenetics treatment provides a novel integrative cell therapy with comprehensive regenerative benefits after stroke. [ABSTRACT FROM AUTHOR]