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.
Highlights
Www.nature.com/scientificreports schizophrenia which contributes to cognitive symptoms[8]
In this study we developed and validated a novel, low power, waxing-and-waning optogenetic stimulation paradigm which, unlike a single pulse laser stimulation used by us and others[30], induced spindles that were indistinguishable from spontaneously occurring sleep spindles that are detected by an automated algorithm which was developed and validated in-house[31]
For the first time we show that sleep spindle density is reduced by activation of a major inhibitory input to thalamic reticular nucleus (TRN) arising from basal forebrain parvalbumin neurons (BF-PV) neurons as well as by localized inhibition of the T-type calcium channels in TRN, implicated as risk factors by genetic studies, using intracerebral reverse microdialysis infusion of the selective T-type inhibitor TTA-P2
Summary
Www.nature.com/scientificreports schizophrenia which contributes to cognitive symptoms[8]. Genetic studies[16,17] have implicated CACNAI1, a gene encoding the low-threshold calcium channel CaV3.3 which is highly expressed in TRN and responsible for the rebound burst discharge in TRN neurons during sleep[18], as a schizophrenia risk gene Another recent study showed that deletion of the schizophrenia-associated gene, ErbB4, from TRN somatostatin (SOM) neurons impairs sensory selection in mice[19]. For the first time we show that sleep spindle density is reduced by activation of a major inhibitory input to TRN arising from BF-PV neurons as well as by localized inhibition of the T-type calcium channels in TRN, implicated as risk factors by genetic studies, using intracerebral reverse microdialysis infusion of the selective T-type inhibitor TTA-P2
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