Intrinsic dynamics and synaptic inputs control the activity patterns of subthalamic nucleus neuron in health and in Parkinson's disease.

Tuesday, December 13, 2011

Charles J. Wilson, Mark D. Bevan Neuroscience 198:54-68.

Neurons in the subthalamic nucleus occupy a pivotal position in the circuitry of the basal ganglia.  They receive direct excitatory input from the cerebral cortex and the intralaminar nuclei of the thalamus, and directly excite the inhibitory basal ganglia output neurons in the internal segment of the globus pallidus and the substantia nigra. They are also engaged in a reciprocal synaptic arrangement with inhibitory neurons in the external segment of the globus pallidus.  Although once viewed as a simple relay of extrinsic input to the basal ganglia, physiological studies of subthalamic neurons have revealed that activity in these neurons does not directly reflect their pattern of extrinsic excitation.  Subthalamic neurons are autonomously active at rates comparable to those observed in vivo, and they generate complex patterns of intrinsic activity arising from the interactions between voltage sensitive ion channels on the somatodendritic and axonal membranes.  Extrinsic synaptic excitation does not create the firing pattern of the subthalamic neuron, but rather controls the timing of action potentials generated intrinsically.   The dopaminergic innervation of the subthalamic nucleus, although moderate, can directly influence firing patterns by acting both on synaptic transmission and voltage-sensitive ion channels responsible for intrinsic properties.  Furthermore, chronic dopamine depletion in Parkinson's disease may modify both synaptic transmission and integration in the subthalamic nucleus, in addition to its effects on other regions of the basal ganglia.

Figure 1.  Spontaneous activity of STN neurons in slices.

A.  photomicrograph of a biocytin-filled subthalamic neuron in coronal section.  B.  Spontaneous activity and interspike interval trajectory.  C.  Voltage clamp recording of persistent ionic currents evoked in an STN neuron during a slow (1 s.) depolarizing ramp.  The control current (black) does not show an equilibrium potential in the subthreshold range.  After ttx treatment (1 µM), the persistent inward current is abolished and the cell acquires a resting potential near -55 mV (blue).  The ttx-sensitive current (red) activates over the voltage range visited by the membrane potential during the interspike interval trajectory.  Average of 25 traces.  The voltage protocol is shown in the inset.

Figure 2.  Contribution of axonal Nav channels to autonomous STN activity. 

A. Effects of 50 ms applications of low [Na+] artificial cerebrospinal fluid (ACSF) (green) to the soma, axon initial segment (ais) and dendrite (d) of a STN neuron.  Upper panel, sites of low [Na+] application (green circles).  The ais is distinguished by its fine caliber and retraction ball at the point of transection.  Left lower panels, action potentials at threshold (dots) under control conditions (black) and following low [Na+] ACSF application (green).  Right lower panels, changes in action potential threshold (relative to mean threshold) under control conditions (black; 5 trials) and following low [Na+] ACSF application (green; 5 trials).  Application of low [Na+] ACSF to the ais 30 μm from the soma consistently elevated action potential threshold compared to the effects of somatic or dendritic application.  B. Upper panels, spike-triggered averages of 100 autonomous action potentials recorded with somatic whole-cell (black traces) and dendritic (blue traces) or axonal (red traces) loose-seal cell-attached electrodes.  In order to discriminate between the axonal and somatodendritic action potential components the second derivative of the whole-cell record is displayed.  Since the loose-seal cell-attached recording approximates the first derivative of the membrane potential that signal was further differentiated to be consistent with the second derivative of the somatic whole-cell record. Thus, the peak of the first temporal derivative of the dendritic loose-seal recording (blue dotted line) follows the first peak of the second temporal derivative of the whole-cell record (black dotted line), whereas the peak of the first temporal derivative of the axonal loose-seal recording (red dotted line) precedes the first peak of the second temporal derivative of the whole-cell record.  Lower panel, latency of the first peak of the second derivative of the somatic action potential relative to the peak of the first derivative of the cell-attached record plotted against the distance of the loose-seal cell-attached recording electrode from the soma. Distances of cell-attached recordings from the soma are plotted as negative and positive for dendrites (n = 14) and axons (n = 24), respectively. The points drawn from the upper examples are highlighted.  Note that action potentials were first detected in the proximal axon.  C. A Golgi labeled STN neuron.  The axon is labeled up to ~ 40 μm from the soma (red arrow), which corresponds to the non-myelinated ais, where action potentials are first initiated.

Figure 3.  Firing rate dependence on constant current.

 A.  1 s current pulses produce high frequency firing with relatively little spike frequency adaptation.  After high frequency firing, there is a pause in spontaneous firing.  B.  Frequency-intensity relationship for the same cell shown in A.  The mean firing rate vs current relationship for 1 s current pulses is sigmoidal in shape (blue) with a maximum sensitivity between 100 and 150 Hz firing rates.  The rate defined by the first interspike interval in the response to the current pulse is shown in red.  The deviation between this curve and the mean rate curve indicates that firing accelerated during the response.  C.  Instantaneous firing rate during the traces shown in A, showing the acceleration in firing at currents beyond 200 pA.  D.  Slow spike frequency adaptation in response to a much longer current pulse than used in A.  After the initial acceleration, spike frequency very gradually decreases to a fraction of the initial rate.  After cessation of the current pulse, spontaneous activity is silenced for about 20 seconds, and then gradually returns. 

Figure 4.  Plateau potentials and bursting occasionally seen in STN neurons.

A. Prolonged high frequency firing triggered by a rebound burst after a hyperpolarizing pulse.  Firing rate is elevated for more than 1 s following the rebound.  B.  Plateau potential and high frequency firing following the offset of a depolarizing current pulse, which gradually decays to baseline levels.  C.  Rhythmic bursting during hyperpolarization caused by recovery from high frequency prolonged firing as in Figure 3D. 

Figure 5.  Resetting of spontaneous firing by excitatory and inhibitory synaptic stimulation.

A. (top)  Superimposition of 50 trials applying a strong stimulation of the internal capsule at the arrow, in the presence of picrotoxin (150 µM) and CGP-55845 (2 µM) to block GABAA and GABAB receptors respectively.  The resulting EPSP triggers action potentials on nearly every trial, but with variable latency.  The evoked action potential is followed by resumption of spontaneous firing at its normal interspike interval, thus resetting rhythmic firing.  (bottom) Three trials are superimposed, showing the phase-sensitivity of firing latency of in response to the stimulus.  A trial in which the EPSP arrives near the end of the interspike interval (red trace) results in an almost immediate action potential, whereas a trial in which the stimulus arrives near the beginning of the interspike interval (blue trace ) produces a longer-latency response.  A trial in which the stimulus falls at an intermediate latency (black trace) produces a response at intermediate latency.  These phase relationships are preserved in the next cycle of spontaneous firing.  B. (top) Superimposition of 50 trials applying a similar strong stimulus, but in the presence of DNQX (20 µM) and APV (50 µM) to block AMPA and NMDA receptors respectively.  A strong IPSP hyperpolarizes the neuron on each trial, and produces a pause in firing approximately the same duration as the spontaneous interspike interval.  (bottom)  Three trials are superimposed, showing the phase sensitivity of the interspike interval following inhibition.  A trial in which the IPSP arrives almost at the end of the interspike interval (red trace) produces the smallest delay in the resumption of firing.  A trial in which the stimulus arrives near the beginning of the interspike interval (blue trace) produces a longer subsequent interspike interval.  An intermediate stimulus arrival time (black) produces an intermediate result.  These phase relationships will be preserved on subsequent cycles.

Figure 6. Dopaminergic neuromodulation of the STN

A. Tyrosine hydroxylase (TH)-immunoreactive (putative dopaminergic) axon terminals in a sagittal section of the STN.  B. Example of a dopamine-immunoreactive axon terminal (asterisk) in the STN that forms a conventional symmetrical synaptic contact (arrow) with the soma (s) of a STN neuron.  C. Local 50 Hz electrical stimulation for 1 second (black bar) leads to the release of dopamine in the STN, as measured by fast-scan cyclic voltammetry.  The level of extracellular dopamine was enhanced by the blockade of the dopamine transporter with GBR12909 (grey trace) compared to control conditions (black trace).  Inset, representative voltammograms.  Peak potentials are indicated (dotted lines) for dopamine oxidation (*) and reduction (**).  D. Application of the D2-like receptor agonist quinpirole (10 μM) to a STN neuron led to depolarization and an increase in the frequency and variability of autonomous firing.  E. D2 receptor-mediated neuromodulation reduced Cav(2.2) channel current that was evoked by an action potential voltage clamp waveform.  F. D2 receptor-mediated inhibition of Cav2.2 channels led to a reduction in SK channel-mediated spike afterhyperpolarization current that was evoked by a 5 ms voltage clamp step from -60 mV to 20 mV.