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Mol Metab. 2017 Apr 22;6(6):594-601. doi: 10.1016/j.molmet.2017.04.005. eCollection 2017 Jun.

Endocannabinoid-dependent disinhibition of orexinergic neurons: Electrophysiological evidence in leptin-knockout obese mice.

Author information

1
Department of Neuroscience Biomedicine and Movement, Section of Physiology and Psychology, University of Verona, 37134 Verona, Italy.
2
National Institute of Neuroscience, 37134 Verona, Italy.
3
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy.

Abstract

OBJECTIVES:

In the ob/ob mouse model of obesity, chronic absence of leptin causes a significant increase of orexin (OX) production by hypothalamic neurons and excessive food intake. The altered OX level is linked to a dramatic increase of the inhibitory innervation of OX producing neurons (OX neurons) and the over expression of the endocannabinoid 2-arachidonoylglycerol (2-AG) by OX neurons of ob/ob mice. Little is known about the function of the excitatory synapses of OX neurons in ob/ob mice, and their modulation by 2-AG. In the present study, we fill this gap and provide the first evidence of the overall level of activation of OX neurons in the ob/ob mice.

METHODS:

We performed in vitro whole-cell patch-clamp recordings on OX neurons located in the perifornical area of the lateral hypothalamus in acute brain slices of wt and ob/ob mice. We identified OX neurons on the basis of their electrophysiological membrane properties, with 96% of concordance with immunohistochemisty.

RESULTS:

We found that OX neurons of ob/ob mice are innervated by less efficient and fewer excitatory synapses than wt mice. Consequently, ob/ob OX neurons show more negative resting membrane potential and lower action potential firing frequency than wt. The bath application of the cannabinoid type-1 receptor agonist WIN55,212-2, depresses both the excitatory and the inhibitory synapses in ob/ob animals, but only the excitatory synapses in wt animals. Finally, the physiologic release of 2-AG induces a prevalent depression of inhibition (disinhibition) of OX neurons in ob/ob animals but not in wt.

CONCLUSIONS:

In ob/ob mice, chronic absence of leptin induces a 2-AG mediated functional disinhibition of OX neurons. This helps explain the increase of OX production and, consequently, the excessive food intake of ob/ob mice.

KEYWORDS:

Endocannabinoids; Leptin; Obesity; Orexin

PMID:
28580289
PMCID:
PMC5444110
DOI:
10.1016/j.molmet.2017.04.005
[Indexed for MEDLINE]
Free PMC Article

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