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. 2025 Sep 11:19:1572258.
doi: 10.3389/fnins.2025.1572258. eCollection 2025.

Mutant mouse models implicate a role for mGluR1/5, prolyl isomerase (Pin1) and Homer1a interactions in wakefulness

Brendan T Keenan  1 , Ewa Strus  1 , Raozhou Lin  2 , May Chan  1 , Jie Lian  1 , Raymond Galante  1 , Paul Worley  2 , Allan I Pack  1   3 , Nirinjini Naidoo  1   3
Affiliations

Mutant mouse models implicate a role for mGluR1/5, prolyl isomerase (Pin1) and Homer1a interactions in wakefulness

Brendan T Keenan et al. Front Neurosci. .

Abstract

Introduction: Healthy sleep and wake are integral to good health and occur when an organism is able to maintain long bouts of both sleep and wakefulness. Homer proteins have been shown to be important for sleep in both Drosophila and mice. For example, genetic deletion of Homer1a in mice results in failure to sustain long bouts of wakefulness. Homer1a has also been shown to amplify mGluR activity by facilitating binding of the prolyl isomerase Pin1 to mGluR. This study uses mouse models to evaluate whether the Homer1a null sleep phenotype may be dependent on the mGluR-Pin1 interaction and examines sleep/wake behavior.

Methods: EEG recordings were used to determine and compare sleep and wake in three different mouse models and their littermate control mice. Mouse models included: mGluR(TS-AA) knock-in mice in which Pin1 binding is prevented and activity-dependent prolyl isomerization of mGluR is inhibited; mGluR(F-R) knock-in mice in which Homer binding is eliminated but Pin1 binding is allowed; and a Homer1a null, mGluR(F-R) double mutant mouse to evaluate whether Pin1 binding can rescue the Homer1a knock-out phenotype. Sleep-wake behavior was analyzed using traditional summary measures and a spike-and-slab mixture distribution to better characterize microarchitecture.

Results: Knock-in mGluR(TS-AA) mice display a reduced ability to sustain long bouts of wakefulness during the active lights off period, recapitulating part of the previously observed wake phenotype of the Homer1a knock-out mouse. Alteration of the Homer binding site to mGluR in mGluR(F-R) knock-in mice has no effect on the sleep phenotype, whereas crossing the mGluR(F-R) knock-in into the Homer null background resulted in increased duration of long wake bouts, suggesting a restored ability to maintain wakefulness, with other sleep/wake characteristics similar to littermate mice.

Conclusion: These studies highlight the role of Pin1 binding to mGluR as a potential mechanism in the control of sleep/wake behavior. Future studies should explore whether other binding partners of Homer and mGluR also affect sleep and wake.

Keywords: Homer1a; Pin1; mGluR; sleep; wake.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Schematic illustrations of Homer-mGluR and Pin1 proposed interactions during sleep (panel A) and waking (panel B) and in the mGluR(TS-AA) (panel C) and mGluR(F-R) (panel D) knock-in mice.
Figure 2
Figure 2
Total amounts of sleep and wake among mGluR(TS-AA) (n = 7) and wildtype littermate control (n = 7) mice. For lights on/off and per hour of recording, data on minutes of wake (panels A,B), and total (panels C,D), NREM (panels E,F) and REM (panels G,H) sleep are summarized. Consistent with our expectation that mGluR(TS-AA) mice will have a similar sleep/wake as observed in Homer1a KO mice, we see decreased wakefulness and increased sleep amounts in the mGluR(TS-AA) mice during the lights off period. Data are consistent when summarizing the entire lights off period or when comparing the hourly measures. Data presented as mean±SE.
Figure 3
Figure 3
Sleep and wake phenotypes estimated from spike and slab approach in mGluR(TS-AA) (n = 7) and wildtype littermate control (n = 7) mice. Phenotypes describing the number (panel A), proportion of short (panel C), and duration of long (panel E) wake bouts preceded by NREM (e.g., primary wake bouts) and number (panel B), proportion of short (panel D), and duration of long (panel F) NREM bouts preceded by wake (e.g., primary sleep bouts) are illustrated in mGluR(TS-AA) and wildtype control mice. Consistent with our hypothesized reduced ability to maintain wakefulness, mGluR(TS-AA) mice show a greater estimated proportion of short wake bouts preceded by NREM and a smaller proportion of short NREM bouts preceded by wake during lights off. Data on the number of NREM bouts preceded by wake and the duration of long NREM bouts preceded by wake are consistent with more consolidated NREM sleep during lights on for mGluR(TS-AA) mice. Data presented as mean±SE.
Figure 4
Figure 4
Empirical Q-Q plots illustrating the distribution of wake bout durations in each genotype. These plots illustrate the distribution of wake bout durations in 4 s epochs for mGluR(TS-AA) (panel A), mGluR(F-R) (panel B) and Homer1a −/−; mGluR(F-R) (panel C) mice on the Y-axis and wildtype littermates on the X-axis. Identical distributions would fall on the line of identify; the grey area on the plot is the estimated variance around the line of identity (null region). The Q-Q line is indicated in black. Results demonstrate reduced ability to maintain wakefulness in the mGluR(TS-AA) mice, as evidenced by the Q-Q line falling below the null region and a rescued wakefulness phenotype in the Homer1a −/−; mGluR(F-R) mice, as evidenced by the Q-Q line falling above the null region.
Figure 5
Figure 5
Total amounts of sleep and wake among mGluR(F-R) (n = 8) and wildtype littermate control (n = 8) mice. For lights on/off and per hour of recording, data on minutes of wake (panels A, B), and total (panels C, D), NREM (panels E, F) and REM (panels G, H) sleep are summarized. Consistent with expectations, we find no meaningful differences between mGluR(F-R) mice and wildtype mice in the amounts of sleep/wake during lights off. Data show a 7 min increase in the REM sleep during lights on within the mGluR(F-R) mutant mice (SMD = 0.96; p = 0.027), but no differences in the amounts of wake, total sleep or NREM sleep. Data presented as mean±SE.
Figure 6
Figure 6
Sleep and wake phenotypes estimated from spike and slab approach in mGluR(F-R) (n = 8) and wildtype littermate control (n = 8) mice. Phenotypes describing the number (panel A), proportion of short (panel C), and duration of long (panel E) wake bouts preceded by NREM (e.g., primary wake bouts) and number (panel B), proportion of short (panel D), and duration of long (panel F) NREM bouts preceded by wake (e.g., primary sleep bouts) are illustrated in mGluR(F-R) and wildtype control mice. We find no meaningful differences between mGluR(F-R) mice and wildtype mice in sleep/wake microarchitecture. Data presented as mean±SE.
Figure 7
Figure 7
Total amounts of sleep and wake among Homer1a −/−; mGluR(F-R) (n = 6) and wildtype littermate control (n = 8) mice. For lights on/off and per hour of recording, data on minutes of wake (panels A, B), and total (panels C, D), NREM (panels E, F) and REM (panels G, H) sleep are summarized. Consistent with a normalization of the sleep/wake phenotype, we find no meaningful differences between Homer1a −/−; mGluR(F-R) and wildtype control mice in the amounts of sleep/wake during lights off. Data presented as mean±SE.
Figure 8
Figure 8
Sleep and wake phenotypes estimated from spike and slab approach in Homer1a −/−; mGluR(F-R) (n = 6) and wildtype littermate control (n = 8) mice. Phenotypes describing the number (panel A), proportion of short (panel C), and duration of long (panel E) wake bouts preceded by NREM (e.g., primary wake bouts) and number (panel B), proportion of short (panel D), and duration of long (panel F) NREM bouts preceded by wake (e.g., primary sleep bouts) are illustrated in Homer1a −/−; mGluR(F-R) and wildtype mice. Consistent with a normalization or rescue of the sleep/wake phenotype, we see that Homer1a −/−; mGluR(F-R) mice have a greater duration of long wake bouts preceded by NREM during lights off, with a consistent (but smaller magnitude) greater duration during lights on. Other traits are similar in mutant and wildtype mice. Data presented as mean±SE.
Figure 9
Figure 9
Representative blots (A) and quantification of Pin1 (B) and mGluR5(pS1126) (C) levels in cortical lysates of wildtype mice after sleep deprivation (SD), recovery sleep (R) and undisturbed diurnal controls (Ctrl). Pin1 protein expression is not changed by sleep deprivation. Phosphorylated mGluR5 is decreased with recovery sleep. mGluR5(pS1126)SD/R(4/2.5h) versus Ctrl(4/2.5h), *p = 0.047 one-way ANOVA followed by Bonferroni post hoc test; n ≥ 6 mice per group.
Figure 10
Figure 10
Quantification of Homer1a (A), mGluR5 (B) and Pin1 (C) in cortical lysates of mGluR(TS-AA) mice following sleep deprivation (SD). Homer1a and mGluR5 are generally increased with SD in wildtype littermates, compared to no change in mGluR(TS-AA) knock-in mice. Pin1 appears unchanged with state in both wildtype and mGluR(TS-AA) mice. Representative western images shown above graphs; n = 4 mice per group for mGluR, n = 6 mice per group for Homer1a and Pin1.
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