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The Rap1 small GTPase is a critical mediator of the effects of stress on prefrontal cortical dysfunction

Molecular Psychiatry volume 26, pages 3223–3239 (2021)Cite this article

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Abstract

The neural molecular and biochemical response to stress is a distinct physiological process, and multiple lines of evidence indicate that the prefrontal cortex (PFC) is particularly sensitive to, and afflicted by, exposure to stress. Largely through this PFC dysfunction, stress has a characterized role in facilitating cognitive impairment, which is often dissociable from its effects on non-cognitive behaviors. The Rap1 small GTPase pathway has emerged as a commonly disrupted intracellular target in neuropsychiatric conditions, whether it be via alterations in Rap1 expression or through alterations in the expression of direct and specific upstream Rap1 activators and inhibitors. Here we demonstrate that escalating, intermittent stress increases Rap1 in mouse PFC synapses, results in cognitive impairments, and reduces the preponderance of mature dendritic spines in PFC neurons. Using viral-mediated gene transfer, we reveal that the hyper-induction of Rap1 in the PFC is sufficient to drive stress-relevant cognitive and synaptic phenotypes. These findings point to Rap1 as a critical mediator of stress-driven neuronal and behavioral pathology and highlight a previously unrecognized involvement for Rap1 in novelty-driven PFC engagement.

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Fig. 1: Restraint stress alters Rap1 levels and produces cognitive and synaptic aberrations.
Fig. 2: mPFC Rap1 adversely impacts Y-maze spontaneous alternation behavior.
Fig. 3: mPFC Rap1 impairs object-in-place recognition memory.
Fig. 4: Rap1 reduces dendritic spine subtype density in the mPFC.
Fig. 5: Rap1 reduces novelty-mediated induction of IEGs in the mPFC.

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Acknowledgements

This work was supported by the Brain & Behavior Research Foundation NARSAD Young Investigator Award, grant 23711 (to MEC).

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  1. Department of Comparative Biosciences, University of Wisconsin at Madison, Madison, WI, USA

    B. A. Kermath, A. M. Vanderplow, K. J. Bjornson, E. N. Seablom, A. M. Novak, C. R. Bernhardt & M. E. Cahill

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  1. B. A. Kermath
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Kermath, B.A., Vanderplow, A.M., Bjornson, K.J. et al. The Rap1 small GTPase is a critical mediator of the effects of stress on prefrontal cortical dysfunction. Mol Psychiatry 26, 3223–3239 (2021). https://doi.org/10.1038/s41380-020-0835-0

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