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Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy.

ABSTRACT: Brain tumor patients commonly present with epileptic seizures. We show that tumor-associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials at supra-physiological frequencies. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and hence decreased GABA release. These studies uncovered a hitherto unknown role of PNNs as an electrostatic insulator that reduces specific membrane capacitance, functionally akin to myelin sheaths around axons, thereby permitting FSNs to exceed physiological firing rates. Disruption of PNNs may similarly account for excitation-inhibition imbalances in other forms of epilepsy and PNN protection through proteolytic inhibition may provide therapeutic benefits.

SUBMITTER: Tewari BP

PROVIDER: S-EPMC6226462 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy.

Tewari Bhanu P BP Chaunsali Lata L Campbell Susan L SL Patel Dipan C DC Goode Adam E AE Sontheimer Harald H

Nature communications 20181109 1

Brain tumor patients commonly present with epileptic seizures. We show that tumor-associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials ...[more]

PMID: 30413686

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Project description:Fast-spiking (FS) interneurons are important elements of neocortical circuitry that constitute the primary source of synaptic inhibition in adult cortex and impart temporal organization on ongoing cortical activity. The highly specialized intrinsic membrane and firing properties that allow cortical FS interneurons to perform these functions are attributable to equally specialized gene expression, which is ultimately coordinated by cell-type-specific transcriptional regulation. Although embryonic transcriptional events govern the initial steps of cell-type specification in most cortical interneurons, including FS cells, the electrophysiological properties that distinguish adult cortical cell types emerge relatively late in postnatal development, and the transcriptional events that drive this maturational process are not known. To address this, we used mouse whole-genome microarrays and whole-cell patch clamp to characterize the transcriptional and electrophysiological maturation of cortical FS interneurons between postnatal day 7 (P7) and P40. We found that the intrinsic and synaptic physiology of FS cells undergoes profound regulation over the first 4 postnatal weeks and that these changes are correlated with primarily monotonic but bidirectional transcriptional regulation of thousands of genes belonging to multiple functional classes. Using our microarray screen as a guide, we discovered that upregulation of two-pore K leak channels between P10 and P25 contributes to one of the major differences between the intrinsic membrane properties of immature and adult FS cells and found a number of other candidate genes that likely confer cell-type specificity on mature FS cells. Experiment Overall Design: We characterized the transcriptional maturation of genetically labeled FS interneurons in mouse S1 cortex using whole-genome microarrays.mRNA was harvested from manually sorted GFPexpressing neurons dissociated from acutely prepared brain slices at a range of developmental time points (P7, P10, P15, P25, and P40) and subsequently reverse transcribed, amplified, labeled, and hybridized to Affymetrix 430 2.0 whole-genome microarrays (three microarrays from three different animals per condition). We used the G42 transgenic mice described by Chattopadhyaya et al. (2004) for all experiments.

Project description:Striatal fast-spiking interneurons (FSIs) fire in variable-length runs of action potentials at 20-200 spikes/s separated by pauses. In vivo, or with fluctuating applied current, both runs and pauses become briefer and more variable. During runs, spikes are entrained specifically to gamma-frequency components of the input fluctuations. We stimulated parvalbumin-expressing striatal FSIs in mouse brain slices with broadband noise currents added to direct current steps and measured spike entrainment across all frequencies. As the constant current level was increased, FSIs produced longer runs and showed sharper frequency tuning, with best entrainment at the stimulus frequency matching their intrarun firing rate. We separated the contributions of previous spikes from that of the fluctuating stimulus, revealing a strong contribution of previous action potentials to gamma-frequency entrainment. In contrast, after subtraction of the effect inherited from the previous spike, the remaining stimulus contribution to spike generation was less sharply tuned, showing a larger contribution of lower frequencies. The frequency specificity of entrainment within a run was reproduced with a phase resetting model based on experimentally measured phase resetting curves of the same FSIs. In the model, broadly tuned phase entrainment for the first spike in a run evolved into sharply tuned gamma entrainment over the next few spikes. The data and modeling results indicate that for FSIs firing in brief runs and pauses firing within runs is entrained by gamma-frequency components of the input, whereas the onset timing of runs may be sensitive to a wider range of stimulus frequency components.NEW & NOTEWORTHY Specific types of neurons entrain their spikes to particular oscillation frequencies in their synaptic input. This entrainment is commonly understood in terms of the subthreshold voltage response, but how this translates to spiking is not clear. We show that in striatal fast-spiking interneurons, entrainment to gamma-frequency input depends on rhythmic spike runs and is explained by the phase resetting curve, whereas run initiation can be triggered by a broad range of input frequencies.

Dataset Information

Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy.

Publications

Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy.

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