Intrinsic amplification of synaptic inputs to dopamine neurons: Burst firing.

摘要

Dopamine (DA) cell activity is critical for initiating movements in goal-directed tasks. In pathological states like Parkinson's disease, degeneration of substantia nigra DA cells disrupts the voluntary selection of motor tasks. At the other extreme, excessive dopaminergic drive at striatal synapses causes the perseverance of unwanted actions, such as dyskinesias, Obsessive-compulsive disorder, Tourette's syndrome, and drug addiction (Grace et al., 2007). Understanding the cellular physiology of nigral DA cells is crucial for fine-tuning the amount of DA release in numerous neuropsychiatric disorders.;One characteristic feature of DA cells is their bimodal firing property: these neurons can switch from a tonic to a burst mode. Baseline 'tonic' firing releases low levels of dopamine to enable movement, feeding, and approach behaviors (Zhou and Palmiter, 1995; Schultz, 2007). When an unexpected stimulus occurs, DA cells are transiently excited and fire 'bursts' of spikes that release a large amount of transmitter. This 'phasic DA signal' strengthens corticostriatal synapses to reinforce the specific motor action sequences that predicted reward (Mirenowicz and Schultz, 1994; Redgrave and Gurney, 2006). The effect of DA spiking patterns on locomotor behaviors has been studied primarily in the ventral tegmental area and in the context of addiction. It is unclear if substantia nigra DA cell bursting is also required for reinforcement learning or motor control. My goal here is to distinguish how burst firing differs from tonic activity at the level of intrinsic membrane properties. I probed candidate ion channels that may provide targets for genetic manipulation to ultimately determine which behaviors require bursting. While much is known about the cellular basis of tonic firing, very little is known about the mechanisms underlying bursting. It is sometimes assumed that similar mechanisms govern tonic and burst firing, a view that will be challenged in this thesis research.;Excitatory synaptic inputs drive bursting in vivo (Floresco et al., 2003; Lodge and Grace, 2006). Yet intrinsic properties of the DA neuron can profoundly influence synaptic integration. Surprisingly, several intrinsic ion channels, including L-type VGCCs and calcium-activated potassium channels, can be blocked without disruption of bursting. As a result, the membrane properties that shape bursting are largely unknown, and distinct from those governing tonic firing. I hypothesized that transient receptor potential (TRP) channels augment glutamatergic inputs to generate a sustained depolarization needed for bursting. In vitro slice physiology was used here to characterize the intrinsic excitability of DA cells and the interplay between TRP and potassium channels in shaping firing pattern.