Deletion of AMPA receptor GluA1 subunit gene (Gria1) causes circadian rhythm disruption and aberrant responses to environmental cues

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.

Phenotyping Young GluA1 Deficient Mice – A Behavioral Characterization in a Genetic Loss-of-Function Model

“…We have previously detected relevant levels of wheel running activity in young female and male wild-type mice from prepubescent age onward (Reiber et al, 2022). Considering wheel running in GluA1 deficient mice, there exist two studies analyzing the performance of adult Gria1 −/− mice (Maksimovic et al, 2014;Ang et al, 2021). In line with our findings in adolescent Gria1 −/− mice, Maksimovic et al (2014) found no significant genotype-related difference during adulthood considering the distance run in the wheel.…”

“…Considering bench-top assessment, GluA1 deficient adult mice have been observed to show normal locomotor activity during continuous light/dark phase monitoring (Fitzgerald et al, 2010;Procaccini et al, 2011). However, as recently reported by Ang et al (2021), Gria1 −/− mice displayed significantly reduced locomotor activity in the dark phase and increased locomotor activity in the light phase as compared to the wild-type control group, indicating relevant circadian rhythm abnormalities related to the genetic deficiency. Thus, although hyperlocomotion and increased resting durations in the zone 'feeding' observed in adolescent Gria1 −/− mice may be linked to lower post-weaning body weights, the activity levels measured are likely to be biased due to the selected short observation interval.…”

“…In line with our findings in adolescent Gria1 −/− mice, Maksimovic et al (2014) found no significant genotype-related difference during adulthood considering the distance run in the wheel. Ang et al (2021) reported moderately reduced levels of overall wheel running activity in Gria1 −/− mice with a significant activity reduction during the dark phase, suggesting relevant circadian rhythm impairments. Interestingly, a correlation between saccharin preference -which likewise represents a highly self-rewarding behavior -and voluntary wheel running activity has been described for wild-type mice, which reduced their intake of sucrose when simultaneously offered a freely accessible running wheel (Maksimovic et al, 2014).…”

Comparative Severity Assessment of Genetic, Stress-Based, and Pharmacological Mouse Models of Depression

“…All models have been shown to induce defined syndromes in mice, leading to alterations in the animals’ emotional or cognitive behaviors. GluA1 knockout mice represent a well-known animal model for depression based on mutation of the AMPA receptor subunit 1 ( Zamanillo et al, 1999 ; Bannerman et al, 2004 ; Chourbaji et al, 2008 ; Wiedholz et al, 2008 ; Sanderson et al, 2009 , 2017 ; Fitzgerald et al, 2010 ; Inta et al, 2010 ; Bygrave et al, 2016 , 2019 ; Eltokhi et al, 2020 ; Ang et al, 2021 ), which is consistent with the glutamate hypothesis of depression ( Sanacora et al, 2012 ). As stress-based models, we used the daily experience of restraint stress on the one hand and on the other, chronic pharmacological treatment with the stress hormone corticosterone ( Moda-Sava et al, 2019 ).…”

“…The loss of GluA1 leads to an increase in depression-associated learned helplessness ( Chourbaji et al, 2008 ), hyperlocomotion in the open field ( Wiedholz et al, 2008 ), novelty- and stress-induced locomotor hyperactivity, altered coping in the forced swim test and in approach-avoidance conflict tests ( Fitzgerald et al, 2010 ), cognitive impairments in short-term memory, puzzle-solving and attention ( Zamanillo et al, 1999 ; Bannerman et al, 2004 ; Sanderson et al, 2009 ; Ben Abdallah et al, 2011 ; Austen et al, 2021 ; Strickland et al, 2021 ). In addition, they show circadian disturbances, striking rest-activity pattern changes, and even reduced voluntary running ( Ang et al, 2021 ), another valuable home cage-based parameter for well-being ( Mallien et al, 2020 ; Weegh et al, 2020 , 2021 ).…”