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Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress

Molecular Psychiatry volume 26, pages 2286–2298 (2021)Cite this article

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Abstract

Post-traumatic stress disorder (PTSD) is characterized by persistent fear memory of remote traumatic events, mental re-experiencing of the trauma, long-term cognitive deficits, and PTSD-associated hippocampal dysfunction. Extinction-based therapeutic approaches acutely reduce fear. However, many patients eventually relapse to the original conditioned fear response. Thus, understanding the underlying molecular mechanisms of this condition is critical to developing new treatments for patients. Mutations in the neuropsychiatric risk gene CACNA1C, which encodes the Cav1.2 isoform of the L-type calcium channel, have been implicated in both PTSD and highly comorbid neuropsychiatric conditions, such as anxiety and depression. Here, we report that male mice with global heterozygous loss of cacna1c exhibit exacerbated contextual fear that persists at remote time points (up to 180 days after shock), despite successful acute extinction training, reminiscent of PTSD patients. Because dopamine has been implicated in contextual fear memory, and Cav1.2 is a downstream target of dopamine D1-receptor (D1R) signaling, we next generated mice with specific deletion of cacna1c from D1R-expressing neurons (D1-cacna1cKO mice). Notably, D1-cacna1cKO mice also show the same exaggerated remote contextual fear, as well as persistently elevated anxiety-like behavior and impaired spatial memory at remote time points, reminiscent of chronic anxiety in treatment-resistant PTSD. We also show that D1-cacna1cKO mice exhibit elevated death of young hippocampal neurons, and that treatment with the neuroprotective agent P7C3-A20 eradicates persistent remote fear. Augmenting survival of young hippocampal neurons may thus provide an effective therapeutic approach for promoting durable remission of PTSD, particularly in patients with CACNA1C mutations or other genetic aberrations that impair calcium signaling or disrupt the survival of young hippocampal neurons.

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Fig. 1: Cacna1c heterozygous mice display exaggerated remote contextual fear memory.
Fig. 2: Mice with loss of cacna1c in D1R-expressing cells exhibit exaggerated remote contextual fear memory.
Fig. 3: Exaggerated remote contextual fear memory is not due to enhanced spatial memory.
Fig. 4: Loss of cacna1c in D1R-expressing cells reduces the net magnitude of adult hippocampal neurogenesis.

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Data availability

The datasets generated during this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by grants to AMR by the National Institute of Drug Abuse, The Hartwell Foundation and the Paul Fund, and to AAP by the Brockman Foundation, the Elizabeth Ring Mather & William Gwinn Mather Fund, the S. Livingston Samuel Mather Trust, the G.R. Lincoln Family Foundation, and Gordon & Evie Safran. CCB was supported by a T32 grant from NIDA, a TL1 grant from the National Center for Advancing Translation Sciences/NIH, and the Frank & Blanche Mowrer Memorial Fellowship. EV-R was also supported by the Training Program in Free Radical and Radiation Biology from the University of Iowa (T32 CA078586). Some of this material is the result of work supported with resources and the use of facilities at the Louis Stokes VA Medical Center in Cleveland.

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  1. These authors contributed equally: Charlotte C. Bavley, Zeeba D. Kabir

Authors and Affiliations

  1. Pediatric Neurology, Pediatrics, Weill Cornell Medicine of Cornell University, New York, NY, 10065, USA

    Charlotte C. Bavley, Zeeba D. Kabir, Alexander P. Walsh, Maria Kosovsky, Jonathan Hackett, Herie Sun & Anjali M. Rajadhyaksha

  2. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine of Cornell University, New York, NY, 10065, USA

    Charlotte C. Bavley & Anjali M. Rajadhyaksha

  3. Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY, 10065, USA

    Charlotte C. Bavley, Zeeba D. Kabir, Alexander P. Walsh, Jonathan Hackett, Andrew A. Pieper & Anjali M. Rajadhyaksha

  4. Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    Edwin Vázquez-Rosa, Coral J. Cintrón-Pérez, Emiko Miller, Yeojung Koh & Andrew A. Pieper

  5. Department of Psychiatry Case Western Reserve University, Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA

    Edwin Vázquez-Rosa, Coral J. Cintrón-Pérez, Emiko Miller, Yeojung Koh & Andrew A. Pieper

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Contributions

CCB, ZDK, AAP, and AMR designed experiments and wrote the paper. CCB, ZDK, APW, MK, JH, and HS ran behavioral experiments and all treatments. CCB and ZDK analyzed data. EV-R, CJC-P, EM, YK, AAP performed neurogenesis and neuronal survival experiments.

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Correspondence to Andrew A. Pieper or Anjali M. Rajadhyaksha.

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AAP is a consultant for Proneurotech, Inc. All other authors declare no conflicts of interest.

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Bavley, C.C., Kabir, Z.D., Walsh, A.P. et al. Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress. Mol Psychiatry 26, 2286–2298 (2021). https://doi.org/10.1038/s41380-020-0730-8

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