The feeding behaviour of ALS mouse models is modulated by the Ca2+ -activated KCa3.1 channels.

Abstract

BACKGROUND AND PURPOSE\nPatients with amyotrophic lateral sclerosis (ALS) exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour of ALS has not been studied in detail. We here investigated if microglial KCa3.1 is linked to hypothalamic neuroinflammation and affects feeding behaviours in ALS mouse models.\n\n\nEXPERIMENTAL APPROACH\nhSOD1G93A and TDP43A315T mice were treated daily with 120 mg/kg of TRAM-34 or vehicle by intraperitoneal injection from the pre-symptomatic until the disease onset phase. Body weight and food intake were measured weekly by weighing food provided and left in the cage. RT-PCR and immunofluorescence analysis were used to characterize microglia phenotype and the main populations of melanocortin neurons in the hypothalamus of hSOD1G93A and age-matched non-tg mice. The cannabinoid-opioid interactions in feeding behaviour of hSOD1G93A mice were studied using an inverse agonist/antagonist of the cannabinoid receptor CB1 (rimonabant) and μ-opioid receptors (naloxone), respectively.\n\n\nKEY RESULTS\nWe found that treatment of hSOD1G93A mice with the KCa3.1 inhibitor, TRAM-34: i) attenuates the pro-inflammatory phenotype of hypothalamic microglia; ii) increases food intake and promotes weight gain; iii) increases the number of healthy POMC (pro-opiomelanocortin) neurons; iv) changes the expression of cannabinoid receptors (CB1 R), involved in energy homeostasis.\n\n\nCONCLUSIONS AND IMPLICATIONS\nUsing ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for KCa3.1 to counteract weight loss in ALS.