Deletion of the clock gene Period2 (Per2) in glial cells alters mood-related behavior in mice

Abstract

The circadian clock regulates many biochemical and physiological pathways, and lack of clock genes, such as Period (Per) 2, affects not only circadian activity rhythms, but can also modulate feeding and mood-related behaviors. However, it is not known how cell-type specific expression of Per2 contributes to these behaviors. In this study, we find that Per2 in glial cells is important for balancing mood-related behaviors, without affecting circadian activity parameters. Genetic and adeno-associated virus-mediated deletion of Per2 in glial cells of mice leads to reduced despair and anxiety. This is paralleled by an increase of the GABA transporter 2 (Gat2/Slc6a13) and Dopamine receptor D3 (Drd3) mRNA, and a reduction of glutamate levels in the nucleus accumbens (NAc). Interestingly, neuronal Per2 knock-out also reduces despair, but does not influence anxiety. The change in mood-related behavior is not a result of a defective molecular clock, as glial Bmal1 deletion has no effect on neither despair nor anxiety. Exclusive deletion of Per2 in glia of the NAc reduced despair, but had no influence on anxiety. Our data provide strong evidence for an important role of glial Per2 in regulating mood-related behavior.

The Circadian Molecular Machinery in CNS Cells: A Fine Tuner of Neuronal and Glial Activity With Space/Time Resolution

“…Furthermore, also the glial deletion of Per2 gene in mice (GPer2 mouse model) has been found to alter Gats mRNA levels (Martini et al, 2021). Notably, the expression of Gat1 significantly decreased in the hypothalamus of GPer2 mice, whereas that of Gat2 has been reported to increase in the NAc of this mouse model compared to controls (Martini et al, 2021). Together, these findings suggest that astrocytic Bmal1 and glial Per2 may regulate the extracellular GABA concentration through the modulation of Gats mRNA levels.…”

“…In particular, Rora has been found to upregulate D3 receptor transcription, whereas Rev-erbα has been reported to periodically inhibit its expression (Ikeda et al, 2013). Moreover, in the nucleus accumbens (NAc), D3 receptors have been found to be regulated also by glial Per2 (Martini et al, 2021). Indeed, mice with a deletion of Per2 in glial cells showed an increase in D3 receptor mRNA levels compared to control animals (Martini et al, 2021).…”

“…Moreover, in the nucleus accumbens (NAc), D3 receptors have been found to be regulated also by glial Per2 (Martini et al, 2021). Indeed, mice with a deletion of Per2 in glial cells showed an increase in D3 receptor mRNA levels compared to control animals (Martini et al, 2021). In particular, Per2 has been suggested to interact with several nuclear receptors, such as Rev-erbα and, to a lesser extent, with Rora (Schmutz et al, 2010), both interacting with the D3 receptor's promoter and consequently modulating D3 receptor expression (Ikeda et al, 2013).…”

“…The impairment of GABA levels has been related to the deletion of astrocytic Bmal1 that decreased the expression of GABA transporters Gat1 and Gat3 in the SCN and in astrocytes, in turn reducing extracellular GABA clearance (Barca-Mayo et al, 2017). Furthermore, also the glial deletion of Per2 gene in mice (GPer2 mouse model) has been found to alter Gats mRNA levels (Martini et al, 2021). Notably, the expression of Gat1 significantly decreased in the hypothalamus of GPer2 mice, whereas that of Gat2 has been reported to increase in the NAc of this mouse model compared to controls (Martini et al, 2021).…”

The Ventral Tegmental Area and Nucleus Accumbens as Circadian Oscillators: Implications for Drug Abuse and Substance Use Disorders

“…Alongside these behavioral effects, loss of NAc astrocyte molecular clock function also disrupts metabolic homeostasis in the NAc and alter glutamatergic synaptic transmission onto neighboring MSNs ( Becker-Krail et al, 2022a ). In addition to regulating reward-related behavior, altering but not disrupting NAc glial molecular clock function (i.e., Per2 deletion) is sufficient to alter mood-related behavior through reducing behavioral despair ( Martini et al, 2021 ). Finally, although preclinical findings suggest disrupted NAc molecular rhythms are associated with altered reward and drug abuse, whether molecular rhythms are disrupted in brains of people with SUD is largely understudied.…”