Chemical transmission between dopaminergic neuron pairs

Abstract

Midbrain dopaminergic (DAergic) neurons play a major regulatory role in in goal-directed behavior and reinforcement learning. DAergic neuron activity, and therefore spatiotemporal properties of dopamine release, precisely encodes reward signals. Neuronal activity is shaped both by external afferences and local interactions (chemical and electrical transmissions). Numerous hints suggest the existence of chemical interactions between DAergic neurons, but direct evidence and characterization are still lacking. Here, we show, using dual patch-clamp recordings in rat brain slices, a widespread bidirectional chemical transmission between DAergic neuron pairs. Hyperpolarizing postsynaptic potentials were partially mediated by D2-like receptors, and entirely resulted from the inhibition of the hyperpolarization-activated depolarizing current (Ih). These results constitute the first evidence in paired recordings of a chemical transmission relying on conductance decrease in mammals. In addition, we show that chemical transmission and electrical synapses frequently coexist within the same neuron pair and dynamically interact to shape DAergic neuron activity.electrical synapses ͉ paired recordings ͉ substantia nigra pars compacta ͉ Ih T he substantia nigra pars compacta (SNc) is the main modulatory nucleus of basal ganglia, a network of subcortical nuclei involved in procedural learning and habit formation (1, 2). Dopaminergic (DAergic) neurons composing SNc mainly project to the dorsal striatum, the major input nucleus of basal ganglia. In striatum, dopamine (DA) potently modulates the processing of corticostriatal information (3-5), contributing to the formation of sensory-motor linkages allowing selection of adapted motor behavior in response to environmental cues.Nigrostriatal DAergic neurons display two modes of discharge: a tonic firing associated with a low but constant DA release supporting a permanent tune-up of the striatal network, and a phasic firing leading to peaks of DA release, coding for a predictive reward value and attention to salient environmental events (6-9). These modes of activity are controlled by intrinsic electrophysiological properties, external inputs, and local interactions (chemical and electrical synapses) between DAergic neurons. SNc DAergic neurons are connected by gap junctions (10), and display electrical coupling able to control their spontaneous tonic activity (11). Yet, electrical coupling might not be their sole mode of communication. Numerous hints strongly support the existence of chemical transmission. DAergic neurons are known to release DA from dendrites (12), bear autoreceptors, and display a characteristic hyperpolarization in response to DA (13,14) or DA agonist application (15, 16), and to electrical stimulation of the SNc (17) or the subthalamus (18). Moreover, ultrastructural studies revealed the presence of dendrodendritic synaptic contacts between DAergic cells in the SNc (19,20). However, a direct demonstration of neuron-to-neuron communication allowing the characteriza...

Ca2+/cAMP-Sensitive Covariation ofIAandIHVoltage Dependences Tunes Rebound Firing in Dopaminergic Neurons

“…10) and could play a critical role in shaping the response of these neurons to inhibitory inputs. Indeed, 70% of the synaptic inputs received by SNc dopaminergic neurons are GABAergic (Tepper and Lee, 2007), while dopamine release between neighboring cells is also responsible for long hyperpolarizations (Vandecasteele et al, 2008). A recent study using dynamic clamp in SNc dopaminergic neurons demonstrated that their response to trains of simulated GABAergic inputs was influenced by I H properties (Tateno and Robinson, 2011).…”

Somatodendritic Dopamine Release Requires Synaptotagmin 4 and 7 and the Participation of Voltage-gated Calcium Channels

“…autoreceptor activation (6,7) and increases firing activity of SN pars reticulata ␥-aminobutyric acid-releasing neurons, a process that might activate feedback signals regulating DA neuron activity (8), thereby influencing axonal DA release.…”

Addictive neurons

“…When MP is held at −75 mV (by −95 pA) 50 µM ZD7288 does not alter evoked APs waveforms and rates in neuron 1 and related SEH in postsynaptic cells held at −80 mV (−220 pA). Interestingly, 'once cell2 had been depolarized at −60 mV, ZD7288 became effective and abolished the SEH' [18] . This is indeed an important result, but the MP of 2 nd cell is denoted to be −85 mV and also considerably less current was injected (−90 vs. −220 pA).…”

“…DA neurons of SNc have a depolarized RMP − resting membrane potential and in order to repolarize to −60 mV a negative current of ~65 pA is injected [18] . Upon the hyperpolarizing steps of −90 pA these neurons exhibit a sag (see Figure 4) with a maximal amplitude of ~20 mV during 1 s. No gap junction response was observed among the pairs of DA neurons, but there was either a train of APs or a single spike-evoked hyperpolarization (SEH) that was heterogeneous in terms of amplitudes.…”