Alterations in TRN-anterodorsal thalamocortical circuits affect sleep architecture and homeostatic processes in oxidative stress vulnerable Gclm−/− mice

Abstract

Schizophrenia is associated with alterations of sensory integration, cognitive processing and both sleep architecture and sleep oscillations in mouse models and human subjects, possibly through changes in thalamocortical dynamics. Oxidative stress (OxS) damage, including inflammation and the impairment of fast-spiking gamma-aminobutyric acid neurons have been hypothesized as a potential mechanism responsible for the onset and development of schizophrenia. Yet, the link between OxS and perturbation of thalamocortical dynamics and sleep remains unclear. Here, we sought to investigate the effects of OxS on sleep regulation by characterizing the dynamics of thalamocortical networks across sleep-wake states in a mouse model with a genetic deletion of the modifier subunit of glutamate-cysteine ligase (Gclm knockout, KO) using high-density electrophysiology in freely-moving mice. We found that Gcml KO mice exhibited a fragmented sleep architecture and impaired sleep homeostasis responses as revealed by the increased NREM sleep latencies, decreased slow-wave activities and spindle rate after sleep deprivation. These changes were associated with altered bursting activity and firing dynamics of neurons from the thalamic reticularis nucleus, anterior cingulate and anterodorsal thalamus. Administration of N-acetylcysteine (NAC), a clinically relevant antioxidant, rescued the sleep fragmentation and spindle rate through a renormalization of local neuronal dynamics in Gclm KO mice. Collectively, these findings provide novel evidence for a link between OxS and the deficits of frontal TC network dynamics as a possible mechanism underlying sleep abnormalities and impaired homeostatic responses observed in schizophrenia.

Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances

“…[68][69][70][71][72][73] In addition, several preclinical models relevant to the study of neuropsychiatric illnesses have also noted reduced sleep spindle density in rodents. 43,74,75 Of note is that sleep spindle spectra power during KYNA elevation was initially reduced in the lower sigma range and, perhaps as a consequence of an increased cortical drive to ameliorate reduced spindle density, the power spectra was then elevated in the upper sigma range in male subjects. 76 Yet importantly, prophylactic treatment with PF-04859989 effectively ameliorated kynurenine-induced sleep deficiencies.…”

A Thalamocortical Perspective on Sleep Spindle Alterations in Neurodevelopmental Disorders

“…Aside from the TRN, non-sensory thalamocortical networks including the intralaminar and central medial thalamus, anterior dorsal, and frontal cortices have received relatively less investigation. However, both animal models and human studies have demonstrated that sleep spindles are involved in the regulation of cognitive functions such as attention, executive control, and higher-order sensory processing [ 10 , 14 , 15 , 66 – 69 ]. While there are signs of common regulatory processes with sensory networks, molecular, genetic investigations have found distinct components and signaling pathways that drive the formation of non-sensory thalamocortical circuits [ 11 , 17 , 60 – 62 , 71 , 72 ].…”

N‐acetylcysteine for schizophrenia: A systematic review and meta‐analysis

“…Glutamate‐cysteine ligase is the key glutathione synthesis 1 . Treatment with N ‐acetylcysteine, a precursor of endogenous antioxidant glutathione that possesses antioxidant, anti‐inflammatory, and neuroprotective properties, restored these abnormalities 1 . Recently, two meta‐analyses were conducted on individuals with schizophrenia (Table S1).…”

“…Recently, glutamate‐cysteine ligase knockout mice demonstrated that abnormal sleep–wake cycle such as sleep fragmentation and a reduction of sleep spindle in which were observed in individuals with schizophrenia 1 . Glutamate‐cysteine ligase is the key glutathione synthesis 1 .…”

“…Recently, glutamate‐cysteine ligase knockout mice demonstrated that abnormal sleep–wake cycle such as sleep fragmentation and a reduction of sleep spindle in which were observed in individuals with schizophrenia 1 . Glutamate‐cysteine ligase is the key glutathione synthesis 1 . Treatment with N ‐acetylcysteine, a precursor of endogenous antioxidant glutathione that possesses antioxidant, anti‐inflammatory, and neuroprotective properties, restored these abnormalities 1 .…”