Journal article Open Access

Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice.

Ooms, Maarten; Rietjens, Roma; Rangarajan, Janaki Raman; Vunckx, Kathleen; Valdeolivas, Sara; Maes, Frederik; Himmelreich, Uwe; Fernandez-Ruiz, Javier; Bormans, Guy; Van Laere, Koen; Casteels, Cindy


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{
  "DOI": "10.1016/j.neurobiolaging.2014.06.010", 
  "container_title": "Neurobiol Aging. ", 
  "title": "Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice.", 
  "issued": {
    "date-parts": [
      [
        2014, 
        6, 
        16
      ]
    ]
  }, 
  "abstract": "<p>Purpose: Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase&nbsp;10A (PDE10A) signaling in Huntington disease (HD). Using [18F]MK-9470 and [18F]JNJ42259152&nbsp;small-animal PET, we investigated for the first time cerebral changes in type 1 cannabinoid (CB1)&nbsp;receptor binding and PDE10A levels in vivo in pre-, early- and late symptomatic HD (R6/2) mice, in&nbsp;relation to glucose metabolism ([18F]FDG PET), brain morphology (MRI) and motor function.&nbsp;</p>\n\n<p>Methods:&nbsp;Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4&nbsp;and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to&nbsp;Paxinos space and analyzed voxel-wise. Volumetric microMRI imaging was performed to assess HD&nbsp;pathology.&nbsp;</p>\n\n<p>Results: In R6/2 mice, CB1 receptor binding was decreased in comparison to WT in a&nbsp;cluster comprising the bilateral caudate-putamen, globus pallidus and thalamic nucleus at week 5 (-8.1&plusmn;2.6%; p=1.7.10-5). Longitudinal follow-up showed further progressive decline compared to controls&nbsp;in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior&nbsp;colliculus, thalamic nucleus and cerebellum (late vs. presymptomatic age: -13.7&plusmn;3.1% for R6/2 and&nbsp;+1.5&plusmn;4.0% for WT; p=1.9.10-5). In R6/2 mice, PDE10A binding potential also decreased over time, to&nbsp;reach significance at early and late symptomatic HD (late vs. presymptomatic age: -79.1&plusmn;1.9% for&nbsp;R6/2 and +2.1&plusmn;2.7% for WT; p=1.5.10-4). The observed changes in CB1 receptor and PDE10A binding&nbsp;were correlated to anomalies exhibited by R6/2 animals in motor function, while no correlation was&nbsp;found with MRI-based striatal volume.&nbsp;</p>\n\n<p>Conclusion: Our findings point to early regional dysfunctions in&nbsp;endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus,&nbsp;that may play a role in the progression of the disease in R6/2 animals. PET quantification of in vivo&nbsp;CB1 and/or PDE10A binding may thus be useful early biomarkers for HD. Our results also provide&nbsp;evidence of subtle motor deficits at earlier stages than previously described.</p>", 
  "author": [
    {
      "given": "Maarten", 
      "family": "Ooms"
    }, 
    {
      "given": "Roma", 
      "family": "Rietjens"
    }, 
    {
      "given": "Janaki Raman", 
      "family": "Rangarajan"
    }, 
    {
      "given": "Kathleen", 
      "family": "Vunckx"
    }, 
    {
      "given": "Sara", 
      "family": "Valdeolivas"
    }, 
    {
      "given": "Frederik", 
      "family": "Maes"
    }, 
    {
      "given": "Uwe", 
      "family": "Himmelreich"
    }, 
    {
      "given": "Javier", 
      "family": "Fernandez-Ruiz"
    }, 
    {
      "given": "Guy", 
      "family": "Bormans"
    }, 
    {
      "given": "Koen", 
      "family": "Van Laere"
    }, 
    {
      "given": "Cindy", 
      "family": "Casteels"
    }
  ], 
  "page": "2858-69", 
  "volume": "35", 
  "type": "article-journal", 
  "issue": "12", 
  "id": "16298"
}
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