GDNF Acutely Potentiates Ca²⁺ Channels and Excitatory Synaptic Transmission in Midbrain Dopaminergic Neurons

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is best known for its long-term survival effect on dopaminergic neurons in the ventral midbrain. A recent study showed that acute application of GDNF to these neurons suppresses A-type potassium channels and potentiates neuronal excitability. Here we have characterized the acute effects of GDNF on Ca²⁺ channels and synaptic transmission. GDNF rapidly and reversibly potentiated the high voltage-activated (HVA) Ca²⁺ channel currents in cultured dopaminergic neurons. Analyses of channel kinetics indicate that GDNF decreased the activation time constant, increased the inactivation and deactivation time constants of HVA Ca²⁺ channel currents. Ca²⁺ imaging experiments demonstrate that GDNF facilitated Ca²⁺ influx induced by membrane depolarization. To investigate the physiological consequences of the Ca²⁺ channel modulation, we examined the acute effects of GDNF on excitatory synaptic transmission at synapses made by these dopaminergic neurons, which co-release the transmitter glutamate. Within 3 min of application, GDNF increased the amplitude of spontaneous and evoked excitatory autaptic- or multiple-postsynaptic currents. The frequency as well as the amplitude of miniature excitatory postsynaptic currents was also increased. These results reveal, for the first time, an acute effect of GDNF on synaptic transmission and its potential mechanisms, and suggest that an important function of GDNF for midbrain dopaminergic neurons is the acute modulation of transmission and ion channels.

Driving GDNF expression: The green and the red traffic lights

“…This enhancement of dopamine synthesis likely leads to an increase in quantal release as observed in postnatal dopaminergic neurons in culture (Pothos et al, 1998). Furthermore, GDNF increases dopamine release owing to the enhancement of the excitability of midbrain dopaminergic neurons, which is associated with the inhibition of A-type K + channels (Yang et al, 2001), and potentiates the activation of Ca 2+ channels and excitatory transmission in midbrain neurons (Wang et al, 2003). The neuroprotective effects of exercise on the nigrostriatal system might also be due to other neurotrophic factors, which are known to be up-regulated by exercise and to ameliorate damage in other brain areas, as BDNF and FGF-2 in the hippocampus (Neeper et al, 1995;Gomez-Pinilla et al, 1997;Cotman and Berchtold, 2002).…”

“…GDNF enhances the excitability of midbrain dopaminergic neurons by inhibiting A-type K + channels, a fast action mediated by MAPK activation (Yang et al, 2001). GDNF also potentiates the activation of Ca 2+ channels and excitatory transmission in midbrain neurons (Wang et al, 2003). In addition, it was reported that long-term treatment of neuromus- binding protein frequenin (Wang et al, 2001a).…”

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

“…Differentiation of neuroendocrine PC12 cells with glucocorticoids increased the expression of VSCC, thereby enhancing the frequency of depolarization-induced exocytosis [206]. Additionally, GDNF rapidly and reversibly potentiates VSCC currents as well as exocytosis in cultured dopaminergic neurons [207].…”

“…Though GDNF rapidly and reversibly potentiates voltage-activated Ca 2+ currents as well as the amplitude and frequency of spontaneous and evoked excitatory autaptic currents in dopaminergic neurons [207], GDNF is particularly noted for its delayed (days-weeks), long-term (days-weeks) effects, which occur even after a single administration. A single GDNF administration increases K + -evoked DA overflow throughout the striatum and in primary cultures of dopaminergic neurons, without affecting the release of GABA or the basal levels of DA [38,238,288].…”

intranasal GDNF gene therapy approach for treating Parkinson's disease

“…GDNF in particular has been studied extensively as a potential therapeutic agent for Parkinson's disease. Not only has GDNF been found to increase both the firing rate 45 and excitability 46,47 of dopamine neurons, but it has also been shown to be neuroprotective in virtually all neurotoxin--generated animal models of Parkinson's disease when injected directly into the substantia nigra or striatum 48 .…”