Prostaglandin E ₂ -increased thermosensitivity of anterior hypothalamic neurons is associated with depressed inhibition

Abstract

Temperature responses of anterior hypothalamic neurons are considered key elements in the regulation of the temperature setpoint of homeotherms. We have investigated the sensitivity to warming of cultured neurons of the AH from mice with electrophysiological and immunocytochemical techniques. In control experiments, only Ϸ9% of the 3-to 5-week-old cells exhibited changes of their basic firing rate when the temperature was raised from 37°C to 40°C. This ratio was increased to 27% after the cultures were ''primed'' by adding prostaglandin E 2 (PGE2), an endogenous pyrogen, in the extracellular medium. In these neurons the firing rate was significantly increased, and the frequency of the gamma ␥-aminobutyric acid (GABA) inhibitory postsynaptic potentials was markedly decreased. In contrast, the resting potential and membrane resistance of the recorded cells remained unchanged. PGE 2 was found to decrease the level of phosphorylation of the extracellular signalregulated kinases 1 and 2 in a subset of GABAergic neurons that express the E-prostanoid receptor type 3. Inhibition of ERK1͞2 by U0126 mimicked the effects of PGE 2. These data indicate that PGE2 acts primarily on the excitability of GABAergic presynaptic cells, most likely via alterations of voltage-gated K ؉ channels. Our results also suggest that far from being an inherent property of a specialized class of neurons, the degree of thermosensitivity can be strongly modulated by synaptic activity and is a more adaptive property of hypothalamic neurons than previously thought. N eurons in the preoptic area (PO) and anterior hypothalamus (AH) are involved in regulating body temperature, as indicated by lesion and thermode implant studies (reviewed in ref. 1). In confirmation, electrophysiological recordings in this region have revealed that some cells, termed warm-sensitive, increase their firing rate when the local temperature is raised. However, numerous complicating factors have hampered their analysis. For example, their definition, which often relies on the increase of the firing rate per°C (impulse s Ϫ1 ͞°C) or is expressed as a Q 10 , varies among authors. Furthermore, their proportion relative to the cold-sensitive and thermo-insensitive neurons is in the rather low range of 20-30% (2-6) with extreme values of 10% (7) to 48% (8), despite the fact that all in vitro studies have been carried out in cells presumed to be highly excitable, because of their unusually high extracellular K ϩ . Another complicating factor is that most hypothalamic warm-sensitive neurons also respond to changes in skin and spinal temperatures (3); therefore, they must be viewed as integrators of thermal information.The mechanism of warm-sensitivity is not fully understood. It has been suggested that the depolarizing prepotentials which precede an action potential shorten with warming, thus reducing the interspike interval and increasing the firing rate (7, 9). An A-type K ϩ current, which regulates the firing rate in other neuronal types, could be responsible for the shortening o...

Night eating and obesity in the EP3R-deficient mouse

“…The EP3R-like immunoreactivity is richly expressed in the rodent brain, with the highest density of EP3R receptors in the different hypothalamic nuclei involved in thermoregulation and sleep regulation (48)(49)(50). We have shown that EP3R mediates the effects of PGE 2 , a potent pyrogen, on the thermosensitivity of anterior hypothalamic neurons (51). EP3R-like immunoreactivity is also abundant in monoaminergic nuclei such as the raphe nuclei and locus ceruleus (48), where this prostanoid receptor may affect appetite and feeding through modulation of the serotonergic and noradrenergic signaling.…”

Ceramide mediates the rapid phase of febrile response to IL-1β

“…Indeed, multiple studies show that IL-1␤, both in vivo and in vitro, can rapidly inhibit the spontaneous firing of warm-sensitive neurons (14,15), which, together with cold-sensitive and heat-insensitive POA͞AH neurons, are thought to regulate the body temperature set point (13). Because the cell-penetrating C2-ceramide mimicked the effects of IL-1␤ in vivo, we compared the effects of IL-1␤ and C2-ceramide on the activity and thermosensitivity of cultured warm-sensitive POA͞AH neurons, characterized earlier in detail (16,17). Bath application of IL-1␤ or C2-ceramide, in the presence of the PG synthesis inhibitor indomethacin (10 M), resulted in hyperpolarization and decreased the firing rate of these neurons (effects that developed within 1-2 min) (Fig.…”

Histaminergic Modulation of Body Temperature and Energy Expenditure

“…The thermosensitivity of PO/AH neurons is a plastic property both in vivo and in vitro. It has been found that the thermosensitivity can change rapidly in the presence of the pyrogens PGE2 [4] or IL-1 [5,6]. Slower changes are observed in some warm-sensitive PO/AH neurons which decrease their thermosensitivity during NREM sleep [7].…”

“…The question remains open as to whether all warm-sensitive PO/AH neurons have some intrinsic thermosensitivity or if they can also display thermosensitive firing that is synaptically-driven [10]. We have shown that prostaglandin E2 (PGE2), a well established endogenous pyrogen, increases the thermosensitivity and firing rates of PO/AH neurons by decreasing the frequency of IPSPs [4]. In contrast, IL-1β hyperpolarizes a different set of PO/AH neurons and reduces their thermosensitivity by increasing the frequency of IPSPs and of miniature IPSPs [5,13].…”