Abstract
Dysfunction of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and circadian rhythm disruption. To investigate the role of GluA1 in circadian and sleep behaviour, we used wheel-running, passive-infrared, and video-based home-cage activity monitoring to assess daily rest–activity profiles of GluA1-knockout mice (Gria1−/−). We showed that these mice displayed various circadian abnormalities, including misaligned, fragmented, and more variable rest–activity patterns. In addition, they showed heightened, but transient, behavioural arousal to light→dark and dark→light transitions, as well as attenuated nocturnal-light-induced activity suppression (negative masking). In the hypothalamic suprachiasmatic nuclei (SCN), nocturnal-light-induced cFos signals (a molecular marker of neuronal activity in the preceding ~1–2 h) were attenuated, indicating reduced light sensitivity in the SCN. However, there was no change in the neuroanatomical distribution of expression levels of two neuropeptides―vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP)―differentially expressed in the core (ventromedial) vs. shell (dorsolateral) SCN subregions and both are known to be important for neuronal synchronisation within the SCN and circadian rhythmicity. In the motor cortex (area M1/M2), there was increased inter-individual variability in cFos levels during the evening period, mirroring the increased inter-individual variability in locomotor activity under nocturnal light. Finally, in the spontaneous odour recognition task GluA1 knockouts’ short-term memory was impaired due to enhanced attention to the recently encountered familiar odour. These abnormalities due to altered AMPA-receptor-mediated signalling resemble and may contribute to sleep and circadian rhythm disruption and attentional deficits in different modalities in schizophrenia.
Highlights
Sleep and circadian rhythm disruption (SCRD) is reported frequently in neuropsychiatric diseases and is observed in up to 80% of schizophrenia patients [1,2,3]
Received: 21 January 2021 Revised: 19 October 2021 Accepted: 21 October 2021. They exhibit short-term attentional deficits, impaired pre-pulse we examined suprachiasmatic nuclei (SCN) and motor cortical area M1/M2 cFos signals in inhibition, and novelty-induced hyperlocomotion―all beha- response to nocturnal light [52], as well as the expression of two vioural abnormalities considered relevant to the positive symp- main neuropeptides in the SCN, namely vasoactive intestinal toms of schizophrenia [25,26,27,28]
Rest–activity rhythms under 12:12 LD To assess daily activity and circadian entrainment, GluA1 knockout mice and littermate controls were housed under 12:12 LD
Summary
Sleep and circadian rhythm disruption (SCRD) is reported frequently in neuropsychiatric diseases and is observed in up to 80% of schizophrenia patients [1,2,3]. Unstable and fragmented rest–activity rhythms are reported, indicating there is a strong circadian component to daily behaviour that can be disrupted in this disorder. Of the neurotransmitter systems implicated in neuropsychiatric diseases, the evidence for an aetiological role for glutamate dysfunction in schizophrenia is well-supported both at pathological and genetic levels [6,7,8]. From the latest genome-wide association studies of schizophrenia, glutamate receptor loci have been consistently identified as being associated with the disorder; for example, a particular locus within 500 kb of the Gria gene (hg position, chr5:151941104–152797656) is highly genomewide significant (p = 1.055 × 10−10) [9]. Levels of GluA1 and other glutamatergic transcripts are reduced in post-mortem brain tissues of schizophrenia patients [11,12,13]
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