Cannabinoid Signaling and Risk in Huntington's Disease

Overview

Journal Front Comput Neurosci

Specialty Biology

Date 2022 Sep 19

PMID 36118134

Authors

James Humble

James R Kozloski

Affiliations

Soon will be listed here.

Abstract

Dysregulated endocannabinoid (eCB) signaling and the loss of cannabinoid receptors (1s) are important phenotypes of Huntington's disease (HD) but the precise contribution that eCB signaling has at the circuit level is unknown. Using a computational model of spiking neurons, synapses, and eCB signaling, we demonstrate that eCB signaling functions as a homeostatic control mechanism, minimizing excess glutamate. Furthermore, our model demonstrates that metabolic risk, quantified by excess glutamate, increases with cortico-striatal long-term depression (LTD) and/or increased cortico-striatal activity, and replicates a progressive loss of cannabinoid receptors on inhibitory terminals as a function of the excitatory/inhibitory ratio.

References

Naydenov A, Sepers M, Swinney K, Raymond L, Palmiter R, Stella N . Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in HD mice. Neurobiol Dis. 2014; 71:140-50. PMC: 4180675. DOI: 10.1016/j.nbd.2014.08.009. View

Younts T, Castillo P . Endogenous cannabinoid signaling at inhibitory interneurons. Curr Opin Neurobiol. 2014; 26:42-50. PMC: 4024354. DOI: 10.1016/j.conb.2013.12.006. View

Miller B, Dorner J, Bunner K, Gaither T, Klein E, Barton S . Up-regulation of GLT1 reverses the deficit in cortically evoked striatal ascorbate efflux in the R6/2 mouse model of Huntington's disease. J Neurochem. 2012; 121(4):629-38. PMC: 3325322. DOI: 10.1111/j.1471-4159.2012.07691.x. View

Wu Y, Kim J, Tawfik V, Lalchandani R, Scherrer G, Ding J . Input- and cell-type-specific endocannabinoid-dependent LTD in the striatum. Cell Rep. 2014; 10(1):75-87. PMC: 4286501. DOI: 10.1016/j.celrep.2014.12.005. View

Bari M, Battista N, Valenza M, Mastrangelo N, Malaponti M, Catanzaro G . In vitro and in vivo models of Huntington's disease show alterations in the endocannabinoid system. FEBS J. 2013; 280(14):3376-88. DOI: 10.1111/febs.12329. View

Pietropaolo S, Bellocchio L, Ruiz-Calvo A, Cabanas M, Du Z, Guzman M . Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington's disease. Neuropharmacology. 2014; 89:368-74. DOI: 10.1016/j.neuropharm.2014.07.021. View

Cachope R . Functional diversity on synaptic plasticity mediated by endocannabinoids. Philos Trans R Soc Lond B Biol Sci. 2012; 367(1607):3242-53. PMC: 3481528. DOI: 10.1098/rstb.2011.0386. View

Cepeda C, Galvan L, Holley S, Rao S, Andre V, Botelho E . Multiple sources of striatal inhibition are differentially affected in Huntington's disease mouse models. J Neurosci. 2013; 33(17):7393-406. PMC: 3686572. DOI: 10.1523/JNEUROSCI.2137-12.2013. View

Plotkin J, Surmeier D . Corticostriatal synaptic adaptations in Huntington's disease. Curr Opin Neurobiol. 2015; 33:53-62. PMC: 4831704. DOI: 10.1016/j.conb.2015.01.020. View

10.

Glass M, van Dellen A, Blakemore C, Hannan A, Faull R . Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience. 2003; 123(1):207-12. DOI: 10.1016/s0306-4522(03)00595-5. View

11.

Fernandez-Ruiz J, Sagredo O, Pazos M, Garcia C, Pertwee R, Mechoulam R . Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?. Br J Clin Pharmacol. 2012; 75(2):323-33. PMC: 3579248. DOI: 10.1111/j.1365-2125.2012.04341.x. View

12.

Dowie M, Bradshaw H, Howard M, Nicholson L, Faull R, Hannan A . Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington's disease. Neuroscience. 2009; 163(1):456-65. DOI: 10.1016/j.neuroscience.2009.06.014. View

13.

Horne E, Coy J, Swinney K, Fung S, Cherry A, Marrs W . Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington's disease and mouse models. Eur J Neurosci. 2012; 37(3):429-40. PMC: 3699342. DOI: 10.1111/ejn.12045. View

14.

Glass M, Dragunow M, Faull R . The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. Neuroscience. 2000; 97(3):505-19. DOI: 10.1016/s0306-4522(00)00008-7. View

15.

Van Laere K, Casteels C, Dhollander I, Goffin K, Grachev I, Bormans G . Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. J Nucl Med. 2010; 51(9):1413-7. DOI: 10.2967/jnumed.110.077156. View

16.

Van Waes V, Beverley J, Siman H, Tseng K, Steiner H . CB1 Cannabinoid Receptor Expression in the Striatum: Association with Corticostriatal Circuits and Developmental Regulation. Front Pharmacol. 2012; 3:21. PMC: 3298893. DOI: 10.3389/fphar.2012.00021. View

17.

Maejima T, Kano M . Endogenous cannabinoid as a retrograde messenger from depolarized postsynaptic neurons to presynaptic terminals. Neurosci Res. 2001; 40(3):205-10. DOI: 10.1016/s0168-0102(01)00241-3. View

18.

Chiodi V, Uchigashima M, Beggiato S, Ferrante A, Armida M, Martire A . Unbalance of CB1 receptors expressed in GABAergic and glutamatergic neurons in a transgenic mouse model of Huntington's disease. Neurobiol Dis. 2011; 45(3):983-91. DOI: 10.1016/j.nbd.2011.12.017. View

19.

Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M . Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009; 89(1):309-80. DOI: 10.1152/physrev.00019.2008. View

20.

Heifets B, Castillo P . Endocannabinoid signaling and long-term synaptic plasticity. Annu Rev Physiol. 2009; 71:283-306. PMC: 4454279. DOI: 10.1146/annurev.physiol.010908.163149. View