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Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na V 1.2 and Na V 1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of Na V channels that exhibit state-dependent block of both Na V 1.2 and Na V 1.6, along with knock-in mice with changes in Na V 1.2 or Na V 1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of Na V 1.2 and Na V 1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting—and in some situations, opposing—effects on neuronal action potential output, with Na V 1.6 block decreasing and Na V 1.2 block increasing output. Thus, Na V isoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide the development of therapeutics designed to temper hyperexcitability through selective Na V isoform blockade.

Single neuron models are fundamental for computational modeling of the brain’s neuronal networks, and understanding how ion channel dynamics mediate neural function. A challenge in defining such models is determining biophysically realistic channel distributions. Here, we present an efficient, highly parallel evolutionary algorithm for developing such models, named NeuroGPU-EA. NeuroGPU-EA uses CPUs and GPUs concurrently to simulate and evaluate neuron membrane potentials with respect to multiple stimuli. We demonstrate a logarithmic cost for scaling the stimuli used in the fitting procedure. NeuroGPU-EA outperforms the typically used CPU based evolutionary algorithm by a factor of 100 on a series of scaling benchmarks. We report observed performance bottlenecks and propose mitigation strategies. Finally, we also discuss the potential of this method for efficient simulation and evaluation of electrophysiological waveforms.

Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability (ID), motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicating the critical role of Syngap1 . Several rodent models with a loss of Syngap1 have been engineered, identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of SYNGAP1/Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the original mouse model from the Huganir laboratory, corroborated behaviors including robust hyperactivity and deficits in learning and memory in young adults. Furthermore, we described impairments in the domain of sleep, characterized using neurophysiological data that was collected with wireless, telemetric electroencephalography (EEG). Syngap1 +/− mice exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta power frequency. For the first time, we illustrated that primary neurons from Syngap1 +/− mice displayed: 1) increased network firing activity, 2) greater bursts, 3) and shorter inter-burst intervals between peaks, by utilizing high density microelectrode arrays (HD-MEA). Our work bridges in vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development and efficacy assessment of targeted treatments for SRID.

The medial prefrontal cortex plays a key role in higher order cognitive functions like decision making and social cognition. These complex behaviors emerge from the coordinated firing of prefrontal neurons. Fast-spiking interneurons (FSIs) control the timing of excitatory neuron firing via somatic inhibition and generate gamma (30–100 Hz) oscillations. Therefore, factors that regulate how FSIs respond to gamma-frequency input could affect both prefrontal circuit activity and behavior. Here, we show that serotonin (5HT), which is known to regulate gamma power, acts via 5HT2A receptors to suppress an inward-rectifying potassium conductance in FSIs. This leads to depolarization, increased input resistance, enhanced spiking, and slowed decay of excitatory post-synaptic potentials (EPSPs). Notably, we found that slowed EPSP decay preferentially enhanced temporal summation and firing elicited by gamma frequency inputs. These findings show how changes in passive membrane properties can affect not only neuronal excitability but also the temporal filtering of synaptic inputs.

Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na V 1.2 and Na V 1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of Na V channels that exhibit state-dependent block of both Na V 1.2 and Na V 1.6, along with knock-in mice with changes in Na V 1.2 or Na V 1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of Na V 1.2 and Na V 1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting—and in some situations, opposing—effects on neuronal action potential output, with Na V 1.6 block decreasing and Na V 1.2 block increasing output. Thus, Na V isoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide the development of therapeutics designed to temper hyperexcitability through selective Na V isoform blockade.

Mature neocortical pyramidal cells functionally express two sodium channel (Na ) isoforms: Na 1.2 and Na 1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of Na channels that exhibit state-dependent block of both Na 1.2 and Na 1.6, along with knock-in mice with changes in Na 1.2 or Na 1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of Na 1.2 and Na 1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting-and in some situations, opposing-effects on neuronal action potential output, with Na 1.6 block decreasing and Na 1.2 block increasing output. Thus, Na isoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide the development of therapeutics designed to temper hyperexcitability through selective Na isoform blockade.

Compartmental modeling is a widely used tool in neurophysiology but the detail and scope of such models is frequently limited by lack of computational resources. Here we implement compartmental modeling on low cost Graphical Processing Units (GPUs), which significantly increases simulation speed compared to NEURON. Testing two methods for solving the current diffusion equation system revealed which method is more useful for specific neuron morphologies. Regions of applicability were investigated using a range of simulations from a single membrane potential trace simulated in a simple fork morphology to multiple traces on multiple realistic cells. A runtime peak 150-fold faster than the CPU was achieved. This application can be used for statistical analysis and data fitting optimizations of compartmental models and may be used for simultaneously simulating large populations of neurons. Since GPUs are forging ahead and proving to be more cost-effective than CPUs, this may significantly decrease the cost of computation power and open new computational possibilities for laboratories with limited budgets.

Folate is crucial for various biological processes, with deficiencies during pregnancy being linked to increased risk for neural tube defects and neurodevelopmental disorders. As a proactive measure, folic acid fortification in foods has been mandated in many countries, in addition to dietary supplementation recommendations during pregnancy. However, the risks of excess prenatal folic acid supply have yet to be fully understood. To better appreciate molecular changes in mouse brain exposed to 5-fold folic acid excess over normal supplementation, we investigated the transcriptome and methylome for alterations in gene networks. RNA-seq analysis of cerebral cortex collected at birth, revealed significant expression differences in 646 genes with major roles in protein translation. Whole genome bisulfite sequencing revealed 910 significantly differentially methylated regions with functions enriched in glutamatergic synapse and glutathione pathways. To explore the physiological consequences of excess prenatal folic acid exposure, we applied high-density microelectrode arrays to record network-level firing patterns of dissociated cortical neurons. Folic acid excess-derived cortical neurons exhibited significantly altered network activity, characterized by reduced burst amplitude and increased burst frequency, indicating compromised network synchronization. These functional deficits align with the observed molecular alterations in glutamatergic synapse pathways, underscoring the potential for excess prenatal folic acid exposure to disrupt developing metabolic and neurological pathways.

-related epilepsy is an autosomal dominant neurodevelopmental disorder with at least 64 known human variants, each with unique electrophysiological and epileptic characteristics. A multi-disciplinary collaboration generated a novel mouse model (C57BL/6- ) carrying the G269S variant, corresponding to human G288S, located within the coding region of the channel pore. Network excitability of cultured cortical neurons from exhibited sustained hyperexcitability and hypersynchronous bursting while neurons showed early excessive bursting followed by network collapse, suggesting excitotoxicity. displayed poor motor coordination, erratic breathing, and increased apneas. Critically, were more susceptible to thermal-induced seizures in early life. In summary, these data: (i) provide a novel mouse model of KCNT1-related epilepsy, (ii) provide strong evidence of neuronal hyperexcitability, (iii) illustrate early-life seizures as a functional outcome measure, and (iv) lay the groundwork for future analysis of neural activity and modeling circuit level dynamics and . Gain-of-function mutations in the sodium-gated potassium channel KCNT1 have been linked to pediatric epilepsy of varying severity. The human variant G288S (G269S in mice) is linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), Epilepsy of Infancy with Migrating Focal Seizures (EIMFS), and other severe developmental epileptic encephalopathies. There are currently no therapeutics to prevent the progression of -related epilepsy, therefore, the scientific community requires a novel mouse model that is well characterized, and to screen and assess targeted therapeutics. Herein, we engineered a novel mouse to assess developmental and adult phenotypes resulting from the G288S/G269S variant, and , to advance translation toward therapeutic testing for individuals with -related epilepsy.