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Thalamic Reticular Nucleus Parvalbumin Neurons Regulate Sleep Spindles and Electrophysiological Aspects of Schizophrenia in Mice.

ABSTRACT: The thalamic reticular nucleus (TRN) is implicated in schizophrenia pathology. However, it remains unclear whether alterations of TRN activity can account for abnormal electroencephalographic activity observed in patients, namely reduced spindles (10-15?Hz) during sleep and increased delta (0.5-4?Hz) and gamma-band activity (30-80?Hz) during wakefulness. Here, we utilized optogenetic and reverse-microdialysis approaches to modulate activity of the major subpopulation of TRN GABAergic neurons, which express the calcium-binding protein parvalbumin (PV), and are implicated in schizophrenia dysfunction. An automated algorithm with enhanced efficiency and reproducibility compared to manual detection was used for sleep spindle assessment. A novel, low power, waxing-and-waning optogenetic stimulation paradigm preferentially induced spindles that were indistinguishable from spontaneously occurring sleep spindles without altering the behavioral state, when compared to a single pulse laser stimulation used by us and others. Direct optogenetic inhibition of TRN-PV neurons was ineffective in blocking spindles but increased both wakefulness and cortical delta/gamma activity, as well as impaired the 40?Hz auditory steady-state response. For the first time we demonstrate that spindle density is markedly reduced by (i) optogenetic stimulation of a major GABA/PV inhibitory input to TRN arising from basal forebrain parvalbumin neurons (BF-PV) and; (ii) localized pharmacological inhibition of low-threshold calcium channels, implicated as a genetic risk factor for schizophrenia. Together with clinical findings, our results support impaired TRN-PV neuron activity as a potential cause of schizophrenia-linked abnormalities in cortical delta, gamma, and spindle activity. Modulation of the BF-PV input to TRN may improve these neural abnormalities.

SUBMITTER: Thankachan S

PROVIDER: S-EPMC6401113 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Thalamic Reticular Nucleus Parvalbumin Neurons Regulate Sleep Spindles and Electrophysiological Aspects of Schizophrenia in Mice.

Thankachan Stephen S Katsuki Fumi F McKenna James T JT Yang Chun C Shukla Charu C Deisseroth Karl K Uygun David S DS Strecker Robert E RE Brown Ritchie E RE McNally James M JM Basheer Radhika R

Scientific reports 20190305 1

The thalamic reticular nucleus (TRN) is implicated in schizophrenia pathology. However, it remains unclear whether alterations of TRN activity can account for abnormal electroencephalographic activity observed in patients, namely reduced spindles (10-15 Hz) during sleep and increased delta (0.5-4 Hz) and gamma-band activity (30-80 Hz) during wakefulness. Here, we utilized optogenetic and reverse-microdialysis approaches to modulate activity of the major subpopulation of TRN GABAergic neurons, wh ...[more]

PMID: 30837664

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Project description:Spike-and-wave discharges and an accompanying loss of consciousness are hallmarks of absence seizure, which is a childhood generalized epilepsy disorder. In absence seizure, dysfunction of the cortico-thalamo-cortico circuitry is thought to engage in abnormal cortical rhythms. Previous studies demonstrated that the thalamic reticular nucleus has a critical role in the formation of normal cortical rhythms; however, whether thalamic reticular nucleus dysfunction leads directly to abnormal rhythms, such as epilepsy, is largely unknown. We found that expressing the inhibitory opsin, archaerhodopsin, including in the thalamic reticular nucleus, caused abnormal cortical rhythms in Pvalb-tetracycline transactivator::tetO-ArchT (PV-ArchT) double transgenic mice. We validated the PV-ArchT line as a new mouse model of absence seizure through physiological and pharmacological analyses, as well as through examining their behavioural features. We then discovered that archaerhodopsin expression exclusively in thalamic reticular nucleus parvalbumin-positive neurons was sufficient to induce cortical spike-and-wave discharges using adeno-associated virus-mediated thalamic reticular nucleus targeting. Furthermore, we found that archaerhodopsin expression impaired rebound burst firing and T-current in thalamic reticular nucleus parvalbumin-positive cells by slice physiology. Although T-current in the thalamic reticular nucleus was impaired, the T-current blocker ethosuximide still had a therapeutic effect in PV-ArchT mice, suggesting a gain of function of T-type calcium channels in this absence seizure model. However, we did not find any over- or misexpression of T-type calcium channel genes in the thalamus or the cortex. Thus, we demonstrated that thalamic reticular nucleus dysfunction led to an absence seizure-like phenotype in mice. In a final set of experiments, we showed that the archaerhodopsin-mediated absence seizure-like phenotype disappeared after the removal of archaerhodopsin by using a time-controllable transgenic system. These data may provide a hint as to why many absence seizures naturally regress.

Dataset Information

Thalamic Reticular Nucleus Parvalbumin Neurons Regulate Sleep Spindles and Electrophysiological Aspects of Schizophrenia in Mice.

Publications

Thalamic Reticular Nucleus Parvalbumin Neurons Regulate Sleep Spindles and Electrophysiological Aspects of Schizophrenia in Mice.

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