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Pharmacogenetic activation of parvalbumin interneurons in the prefrontal cortex rescues cognitive deficits induced by adolescent MK801 administration

Neuropsychopharmacology volume 48, pages 1267–1276 (2023)Cite this article

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Abstract

The cognitive symptoms of schizophrenia (SZ) present a significant clinical burden. They are treatment resistant and are the primary predictor of functional outcomes. Although the neural mechanisms underlying these deficits remain unclear, pathological GABAergic signaling likely plays an essential role. Perturbations with parvalbumin (PV)-expressing fast-spiking (FS) interneurons in the prefrontal cortex (PFC) are consistently found in post-mortem studies of patients with SZ, as well as in animal models. Our studies have shown decreased prefrontal synaptic inhibition and PV immunostaining, along with working memory and cognitive flexibility deficits in the MK801 model. To test the hypothesized association between PV cell perturbations and impaired cognition in SZ, we activated prefrontal PV cells by using an excitatory DREADD viral vector with a PV promoter to rescue the cognitive deficits induced by adolescent MK801 administration in female rats. We found that targeted pharmacogenetic upregulation of prefrontal PV interneuron activity can restore E/I balance and improve cognition in the MK801 model. Our findings support the hypothesis that the reduced PV cell activity levels disrupt GABA transmission, resulting in the disinhibition of excitatory pyramidal cells. This disinhibition leads to an elevated prefrontal excitation/inhibition (E/I) balance that could be causal for cognitive impairments. Our study provides novel insights into the causal role of PV cells in cognitive function and has clinical implications for understanding the pathophysiology and management of SZ.

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Fig. 1: Experimental Design and PV expression in MK801 mice.
Fig. 2: PV-DREADD Validation.
Fig. 3: Prefrontal PV-DREADD activation ameliorates impairments in spatial working memory and cognitive flexibility associated with adolescent MK801 treatment - T-maze.
Fig. 4: Histological Results.
Fig. 5: Administration of MK801 increased the ratio of spontaneous E/IPSC frequency, which was rescued by activation of PV interneurons in the mPFC.

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Acknowledgements

We thank Theresa Connors for instruction in estrus cycle tracking and Andrew Gargiulo for help with the locomotion task.

Funding

These studies were funded by NIH R01MH085666, NIH R21MH111609, NARSAD Independent Award, Pennsylvania Commonwealth 4100072545 (CURE 2016), to W-JG, and The Helen S. Vernik SZ Pilot Research Project Grant through the Drexel Department of Psychiatry.

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Authors and Affiliations

  1. Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA

    Linda A. Chamberlin, Sha-Sha Yang, Erin P. McEachern, Nancy R. Mack, Brielle R. Ferguson & Wen-Jun Gao

  2. MD/PhD program, Drexel University College of Medicine, Philadelphia, PA, USA

    Linda A. Chamberlin

  3. Institute for Translational Brain Research, Department of Neurology, Fudan University, Shanghai, 200032, China

    Sha-Sha Yang

  4. MD program, Drexel University College of Medicine, Philadelphia, PA, USA

    Joshua T. M. Lucas

  5. Interdisciplinary Health Sciences Program, Drexel University College of Medicine, Philadelphia, PA, USA

    Owen W. McLeod II & Claire A. Rolland

  6. 2 Blackfan circle, Cetern for Life Science, Boston, MA, 02115, USA

    Brielle R. Ferguson

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Contributions

LAC and WJG: conceived the project, designed the experiments, and wrote the manuscript. SSY: conducted physiological recording. LAC: conducted immunostaining, electrophysiological recording, surgery, and behavioral test, and analyzed the related data. EPM: behavioral tests (T-Maze and set-shifting). JTML: partial physiological recording. OWM: physiological data analysis. CAR: histological analysis. NRM: comments and manuscript editing and revision. BRF: conceived the project and manuscript editing.

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Correspondence to Brielle R. Ferguson or Wen-Jun Gao.

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Chamberlin, L.A., Yang, SS., McEachern, E.P. et al. Pharmacogenetic activation of parvalbumin interneurons in the prefrontal cortex rescues cognitive deficits induced by adolescent MK801 administration. Neuropsychopharmacol. 48, 1267–1276 (2023). https://doi.org/10.1038/s41386-023-01576-6

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