Orexigenic NPY/ AgRP and anorexigenic POMC/CART neurons sense and respond to changes in energy balance, signalled through nutrient and hormonal routes in opposing ways, NPY being activated and POMC neurons inhibited during negative states of energy balance and vice-versa1. However the ionic mechanisms that allow these neurons to transduce shifts in energy status into changes in neuronal electrical excitability are still not fully understood.
To explore the cellular mechanisms by which NPY and POMC neurons produce opposing changes in electrical excitability to changes in energy status, we investigated the effects of the mitochondrial uncoupling agent 2,4-Dinitrophenol (DNP) on neuronal excitability of these neurons. Whole-cell patch clamp recording techniques were utilised in hypothalamic slices prepared from POMC-eGFP and NPY-hrGFP- expressing adult male mice (6-10 weeks old). DNP (200µM) induced a reversible membrane hyperpolarisation in 88.2% (15/17) of NPY neurons tested, an effect that was blocked by the ATP-sensitive potassium channel (KATP) blocker tolbutamide (200µM; n=8/8). DNP effects on anorexigenic POMC neurones were more diverse, inducing: depolarisation (59.3%, 16/27), hyperpolarisation (33.3%, 9/27) or a biphasic depolarisation followed by hyperpolarisation (7.4%, 2/27). DNP-induced hyperpolarisation in POMC, like NPY neurons, was blocked by tolbutamide (n= 9/9). DNP-induced depolarisation in POMC neurons were mediated via multiple mechanisms, including: block of an inwardly rectifying potassium conductance (KIR), an effect that was sensitive to the KIR blocker barium (100µM; n=6/13); via the Na+K+-ATPase pump, indicated by its sensitivity to ouabain (100µM; n=6/19); via an effect on the Na+/Ca+ exchanger, indicated by its sensitivity to SN-6 (20µM; n=4/15).
These data suggest that NPY and POMC neurons differentially couple electrical excitability to mitochondrial function through multiple ionic mechanisms. These mechanisms are likely crucial components controlling electrical excitability of these neurons and in co-ordinating counter-regulatory responses to changes in energy balance.