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The thalamic reticular nucleus in schizophrenia and bipolar disorder: role of parvalbumin-expressing neuron networks and oxidative stress.

ABSTRACT: Growing evidence points to a disruption of cortico-thalamo-cortical circuits in schizophrenia (SZ) and bipolar disorder (BD). Clues for a specific involvement of the thalamic reticular nucleus (TRN) come from its unique neuronal characteristics and neural connectivity, allowing it to shape the thalamo-cortical information flow. A direct involvement of the TRN in SZ and BD has not been tested thus far. We used a combination of human postmortem and rodent studies to test the hypothesis that neurons expressing parvalbumin (PV neurons), a main TRN neuronal population, and associated Wisteria floribunda agglutinin-labeled perineuronal nets (WFA/PNNs) are altered in SZ and BD, and that these changes may occur early in the course of the disease as a consequence of oxidative stress. In both disease groups, marked decreases of PV neurons (immunoreactive for PV) and WFA/PNNs were observed in the TRN, with no effects of duration of illness or age at onset. Similarly, in transgenic mice with redox dysregulation, numbers of PV neurons and WFA/PNN+PV neurons were decreased in transgenic compared with wild-type mice; these changes were present at postnatal day (P) 20 for PV neurons and P40 for WFA/PNN+PV neurons, accompanied by alterations of their firing properties. These results show profound abnormalities of PV neurons in the TRN of subjects with SZ and BD, and offer support for the hypothesis that oxidative stress may play a key role in impacting TRN PV neurons at early stages of these disorders. We put forth that these TRN abnormalities may contribute to disruptions of sleep spindles, focused attention and emotion processing in these disorders.

SUBMITTER: Steullet P

PROVIDER: S-EPMC5972042 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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The thalamic reticular nucleus in schizophrenia and bipolar disorder: role of parvalbumin-expressing neuron networks and oxidative stress.

Steullet P P Cabungcal J-H JH Bukhari S A SA Ardelt M I MI Pantazopoulos H H Hamati F F Salt T E TE Cuenod M M Do Kim Q KQ Berretta S S

Molecular psychiatry 20171128 10

Growing evidence points to a disruption of cortico-thalamo-cortical circuits in schizophrenia (SZ) and bipolar disorder (BD). Clues for a specific involvement of the thalamic reticular nucleus (TRN) come from its unique neuronal characteristics and neural connectivity, allowing it to shape the thalamo-cortical information flow. A direct involvement of the TRN in SZ and BD has not been tested thus far. We used a combination of human postmortem and rodent studies to test the hypothesis that neuron ...[more]

PMID: 29180672

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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

The thalamic reticular nucleus in schizophrenia and bipolar disorder: role of parvalbumin-expressing neuron networks and oxidative stress.

Publications

The thalamic reticular nucleus in schizophrenia and bipolar disorder: role of parvalbumin-expressing neuron networks and oxidative stress.

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