Glucose Concentrations Modulate Brain-Derived Neurotrophic Factor Responsiveness of Neurons in the Paraventricular Nucleus of the Hypothalamus

Abstract

The hypothalamic paraventricular nucleus (PVN) is critical for normal energy balance and has been shown to contain high levels of both BDNF and TrkB mRNA. Microinjections of BDNF into the PVN increase energy expenditure, suggesting BDNF plays an important role in energy homeostasis through direct actions in this nucleus. The current studies were undertaken to examine the postsynaptic effects of BDNF on the membrane potential of PVN neurons, and to determine if extracellular glucose concentrations modulated these effects.

We used hypothalamic PVN slices from male Sprague-Dawley rats to perform whole cell current-clamp recordings from PVN neurons. BDNF was bath applied at a concentration of 2 nM and the effects on membrane potential determined. BDNF caused depolarizations in 54% of neurons (n = 25; mean ± standard error of the mean 8.9 ± 1.2 mV), hyperpolarizations in 23% (n = 11; -6.7 ± 1.4 mV), while the remaining cells were unaffected. These effects were maintained in the presence of tetrodotoxin (N = 9; 56% depolarized, 22% hyperpolarized, 22% non-responders), or the GABA_a antagonist bicuculline (N = 12; 42% depolarized, 17% hyperpolarized, 41% non-responders), supporting the conclusion that these effects on membrane potential were postsynaptic.

Current-clamp recordings from PVN neurons next examined effects of BDNF on these neurons at varying extracellular glucose concentrations. Larger proportions of PVN neurons hyperpolarized in response to BDNF as glucose concentrations decreased (10 mM glucose 23% (n = 11) of neurons hyperpolarized whereas at 0.2 mM glucose, 71% showed hyperpolarizing effects (n = 12)).

Our findings reveal that BDNF has direct GABA_A independent effects on PVN neurons, which are modulated by local glucose concentrations. The latter observation further emphasizes the critical importance of using physiologically relevant conditions for study of central pathways involved in the regulation of energy homeostasis.

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