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Prefrontal parvalbumin neurons as a target for enhancing cognition in non-pathological and 22q11.2 microdeletion syndrome mice

Molecular Psychiatry (2025)Cite this article

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Abstract

To achieve goals in a dynamic environment, the prefrontal cortex (PFC) facilitates various cognitive functions that allow an organism to detect and discriminate information, identify changes in context, and apply this information to representations of known rules and internal states. A failure of organized communication in the PFC is thought to contribute to the emergence of cognitive impairments in psychiatric diseases, with attentional deficits occurring as a fundamental symptom across various conditions. The 22q11.2 microdeletion syndrome is a rare genetic condition that confers a high risk for developing psychiatric and neurodevelopmental disorders, and mouse models have been shown to display attention impairments and PFC pathology that are relevant to clinical populations. Abnormalities in prefrontal parvalbumin-expressing neurons (PVNs) are part of the observed pathophysiology, and studies in rodents have shown that the direct manipulation of these cells can induce behavioral deficits that align with the cognitive symptoms seen in psychiatric diseases. PVNs are a subclass of GABAergic inhibitory cells that facilitate high frequency oscillations that are associated with information processing in the cortex. Because PVNs have such a pivotal role in organizing the input of information to the PFC, their dysfunction could contribute to the manifestation of a variety of cognitive and behavior impairments in disease states. In the present study, we expanded on the role of PVNs in supporting cognition by investigating their involvement in multiple components of attentional functions using a translationally relevant task of focused visual attention, in both non-pathological mice and a model of the 22q11.2 microdeletion syndrome. Using genetically-encoded calcium sensors, fiber photometry, and optogenetics, we describe a novel assessment of how PVN activity is modulated by learning and acute changes in task demands. Interestingly, we observed that task-evoked prefrontal PVN activity was reduced in mice that exhibited poorer attention and in 22q11.2 mutant mice. While PVN activity was shaped across learning in non-pathological mice, mutant mice exhibited a lack of signal dynamics that coincided with attentional deficits. Importantly, we observed that task performance in both poor performing wild-types and 22q11.2 mutants could be alleviated by high frequency (gamma band range) PVN stimulation. Thus, PVNs appear to be involved in the acquisition of task rules and execution of attention and continue to be a promising therapeutic target for cognitive dysfunction in disease.

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Fig. 1: Prefrontal PVN activity reliably tracks stimulus presentation and correct responses to non-target stimuli.
Fig. 2: Prefrontal PVN activity is altered by acute task demands and associated with task performance.
Fig. 3: Frequency-specific activation of prefrontal PVNs differentially modulates local oscillatory activity.
Fig. 4: Optogenetic disruption of prefrontal PVNs impairs target responding during the 1NT task.
Fig. 5: Gamma stimulation of prefrontal PVNs improves attention in low performing mice on the 4NT task.
Fig. 6: Learning amplifies PVN activity and is absent in a mouse model of the 22q11.2 microdeletion syndrome that displays attention deficits.
Fig. 7: Gamma stimulation of PVNs rescues deficits in discrimination sensitivity in a mouse model of 22q11.2 microdeletion syndrome.

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Data availability

Data is available upon request. Additionally, the datasets generated and analysed in this study will be freely accessible in the Mousebytes repository, https://mousebytes.ca/home.

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Acknowledgements

This research was supported by through the Canada First Research Excellence Fund (CFREF), Brain Canada, the Canadian Institutes of Health Research (CHIR PJT 426966), the Natural Sciences and Engineering Research Council (NSERC RGPIN-2019-06102 RGPIN-2019-06087), the Canada Foundation for Innovation, and the Ontario Research Fund. All figures were created in BioRender. Dexter, T. (2026) https://BioRender.com/csljh96. LMS is the Canada Research Chair in Translational Cognitive Neuroscience and TJB is the Western Research Chair in Behavioural Neuroscience.

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Authors and Affiliations

  1. Neuroscience Graduate Program, Wester University, London, ON, Canada

    Tyler D. Dexter & Shahnaza Hamidullah

  2. Robarts Research Institute, Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada

    Tyler D. Dexter, Daniel Palmer, Shahnaza Hamidullah, Meira M. F. Machado, Timothy J. Bussey & Lisa M. Saksida

  3. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Tyler D. Dexter, Daniel Palmer, Shahnaza Hamidullah, Meira M. F. Machado, Timothy J. Bussey & Lisa M. Saksida

  4. Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Ashley L. Schormans & Brian L. Allman

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  1. Tyler D. Dexter
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Contributions

The project was conceived by T.D.D, T.J.B, L.M.S., and D.P. and supervised by D.P., T.J.B. and L.M.S. T.D.D performed the behavioral experiments, analyzed the data, generated the figures, and wrote the manuscript. T.D.D., T.J.B, and L.M.S edited the manuscript. A.L.S. conducted the electrophysiology experiments, analyzed the data, generated Fig. 4, and wrote the electrophysiology results and methods sections. D.P. wrote custom photometry and optogenetic analysis scripts and provided training and supervision. S.H. assisted in testing mice included in Supplementary Figure 5. T.D.D. and M.M.F.M. processed the brain tissue for histology. M.M.F.M. performed the immunohistochemistry and generated the images. B.L.A. provided insight throughout the project and supervised the electrophysiology experiments.

Corresponding author

Correspondence to Tyler D. Dexter.

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Competing interests

T.J.B. and L.M.S. have established a series of targeted cognitive tests for animals, administered via touchscreen within a custom environment known as the “Bussey-Saksida touchscreen chamber”. Cambridge Enterprise, the technology transfer office of the University of Cambridge, supported commercialisation of the Bussey-Saksida chamber, culminating in a license to Campden Instruments. Any financial compensation received from commercialisation of the technology is fully invested in further touchscreen development and/or maintenance. T.D., D.P., A.L.S., S.H., M.M.F.M., B.L.A. declare no competing interests.

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Dexter, T.D., Palmer, D., Schormans, A.L. et al. Prefrontal parvalbumin neurons as a target for enhancing cognition in non-pathological and 22q11.2 microdeletion syndrome mice. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03386-2

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