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Mark D Bevan

Publications and source records attributed to Mark D Bevan.

10 recordsLinked to original sources

Cellular principles underlying normal and pathological activity in the subthalamic nucleus.

The motor symptoms of Parkinson's disease are associated with abnormal, correlated, low frequency, rhythmic burst activity in the subthalamic nucleus and connected nuclei. Research into the mechanisms controlling the pattern of subthalamic activity has intensified because therapies that manipulate the pattern of subthalamic activity, such as deep brain stimulation and levodopa administration, improve motor function in Parkinson's disease. Recent findings suggest that dopamine denervation of the striatum and extrastriatal basal ganglia profoundly alters the transmission and integration of glutamatergic cortical and GABAergic pallidal inputs to subthalamic neurons, leading to pathological activity that resonates throughout the basal ganglia and wider motor system.

Animals↗

Enhancement of excitatory synaptic integration by GABAergic inhibition in the subthalamic nucleus.

The activity patterns of subthalamic nucleus (STN) neurons, which are intimately related to normal movement and abnormal movement in Parkinson's disease (PD), are sculpted by feedback GABAergic inhibition from the reciprocally connected globus pallidus (GP). To understand the principles underlying the integration of GABAergic inputs, we used gramicidin-based patch-clamp recording of STN neurons in rat brain slices. Voltage-dependent Na+ (Nav) channels actively truncated synthetic IPSPs and were required for autonomous activity. In contrast, hyperpolarization-activated cyclic nucleotide-gated and class 3 voltage-dependent Ca2+ channels contributed minimally to the integration of single or low-frequency trains of IPSPs and autonomous activity. Interestingly, IPSPs modified action potentials (APs) in a manner that suggested IPSPs enhanced postsynaptic Nav channel availability. This possibility was confirmed in acutely isolated STN neurons using current-clamp recordings containing IPSPs as voltage-clamp waveforms. Tetrodotoxin-sensitive subthreshold and spike-associated Na+ currents declined during autonomous spiking but were indeed transiently boosted after IPSPs. A functional consequence of inhibition-dependent augmentation of postsynaptic excitability was that EPSP-AP coupling was dramatically improved when IPSPs preceded EPSPs. Because STN neuronal activity exhibits coherence with cortical beta-oscillations in PD, we tested how rhythmic sequences of cortical EPSPs were integrated in the absence and presence of feedback inhibition. STN neuronal activity was consistently entrained by EPSPs only in the presence of feedback inhibition. These observations suggest that feedback inhibition from the GP is critical for the emergence of coherent beta-oscillations between the cortex and STN in PD.

Animals↗

Ionic mechanisms underlying autonomous action potential generation in the somata and dendrites of GABAergic substantia nigra pars reticulata neurons in vitro.

Through their repetitive discharge, GABAergic neurons of the substantia nigra pars reticulata (SNr) tonically inhibit the target nuclei of the basal ganglia and the dopamine neurons of the midbrain. As the repetitive firing of SNr neurons persists in vitro, perforated, whole-cell and cell-attached patch-clamp recordings were made from rat brain slices to determine the mechanisms underlying this activity. The spontaneous activity of SNr neurons was not perturbed by the blockade of fast synaptic transmission, demonstrating that it was autonomous in nature. A subthreshold, slowly inactivating, voltage-dependent, tetrodotoxin (TTX)-sensitive Na+ current and a TTX-insensitive inward current that was mediated in part by Na+ were responsible for depolarization to action potential (AP) threshold. An apamin-sensitive spike afterhyperpolarization mediated by small-conductance Ca2+-dependent K+ (SK) channels was critical for the precision of autonomous activity. SK channels were activated, in part, by Ca(2+) flowing throughomega-conotoxin GVIA-sensitive, class 2.2 voltage-dependent Ca2+ channels. Although Cs+/ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride)-sensitive hyperpolarization-activated currents were also observed in SNr neurons, they were activated at voltages that were in general more hyperpolarized than those associated with autonomous activity. Simultaneous somatic and dendritic recordings revealed that autonomously generated APs were observed first at the soma before propagating into dendrites up to 120 microm from the somatic recording site. Backpropagation of autonomously generated APs was reliable with no observable incidence of failure. Together, these data suggest that the resting inhibitory output of the basal ganglia relies, in large part, on the intrinsic firing properties of the neurons that convey this signal.

Action Potentials↗

Globus pallidus neurons dynamically regulate the activity pattern of subthalamic nucleus neurons through the frequency-dependent activation of postsynaptic GABAA and GABAB receptors.

Reciprocally connected GABAergic neurons of the globus pallidus (GP) and glutamatergic neurons of the subthalamic nucleus (STN) are a putative generator of pathological rhythmic burst firing in Parkinson's disease (PD). Burst firing of STN neurons may be driven by rebound depolarization after barrages of GABA(A) receptor (GABA(A)R)-mediated IPSPs arising from pallidal fibers. To determine the conditions under which pallidosubthalamic transmission activates these and other postsynaptic GABARs, a parasagittal mouse brain slice preparation was developed in which pallidosubthalamic connections were preserved. Intact connectivity was first confirmed through the injection of a neuronal tracer into the GP. Voltage-clamp and gramicidin-based perforated-patch current-clamp recordings were then used to study the relative influences of GABA(A)R- and GABA(B)R-mediated pallidosubthalamic transmission on STN neurons. Spontaneous phasic, but not tonic, activation of postsynaptic GABA(A)Rs reduced the frequency and disrupted the rhythmicity of autonomous firing in STN neurons. However, postsynaptic GABA(B)Rs were only sufficiently activated to impact STN firing when pallidosubthalamic transmission was elevated or pallidal fibers were synchronously activated by electrical stimulation. In a subset of neurons, rebound burst depolarizations followed high-frequency, synchronous stimulation of pallidosubthalamic fibers. Although GABA(B)R-mediated hyperpolarization was itself sufficient to generate rebound bursts, coincident activation of postsynaptic GABA(A)Rs produced longer and more intense burst firing. These findings elucidate a novel route through which burst activity can be generated in the STN, and suggest that GABARs on STN neurons could act in a synergistic manner to generate abnormal burst activity in PD.

2-Amino-5-phosphonovalerate↗

Synchronous unit activity and local field potentials evoked in the subthalamic nucleus by cortical stimulation.

The responses of single subthalamic nucleus (STN) neurons to cortical activation are complex and depend on the relative activation of several neuronal circuits, making theoretical extrapolation of single neuron responses to the population level difficult. To understand better the degree of synchrony imposed on STN neurons and associated neuronal networks by cortical activation, we recorded the responses of single units, pairs of neighboring neurons, and local field potentials (LFPs) in STN to discrete electrical stimulation of the cortex in anesthetized rats. Stimulation of ipsilateral frontal cortex, but not temporal cortex, generated synchronized "multiphasic" responses in neighboring units in rostral STN, usually consisting of a brief, short-latency excitation, a brief inhibition, a second excitation, and a long-duration inhibition. Evoked LFPs in STN consistently mirrored unit responses; brief, negative deflections in the LFP coincided with excitations and brief, positive deflections with inhibitions. This characteristic LFP was dissimilar to potentials evoked in cortex and structures surrounding STN and was resistant to fluctuations in forebrain activity. The short-latency excitation and associated LFP deflection exhibited the highest fidelity to low-intensity cortical stimuli. Unit response failures, which mostly occurred in caudal STN, were not associated with LFPs typical of rostral STN. These data suggest that local populations of STN neurons can be synchronized by both direct and indirect cortical inputs. Synchronized ensemble activity is dependent on topography and input intensity. Finally, the stereotypical, multiphasic profile of the evoked LFP indicates that it might be useful for locating the STN in clinical as well as nonclinical settings.

Action Potentials↗

Synaptic release of dopamine in the subthalamic nucleus.

The direct modulation of subthalamic nucleus (STN) neurons by dopamine (DA) neurons of the substantia nigra (SN) is controversial owing to the thick caliber and low density of DA axons in the STN. The abnormal activity of the STN in Parkinson's disease (PD), which is central to the appearance of symptoms, is therefore thought to result from the loss of DA in the striatum. We carried out three experiments in rats to explore the function of DA in the STN: (i) light and electron microscopic analysis of tyrosine hydroxylase (TH)-, dopamine beta-hydroxylase (DbetaH)- and DA-immunoreactive structures to determine whether DA axons form synapses; (ii) fast-scan cyclic voltammetry (FCV) to determine whether DA axons release DA; and (iii) patch clamp recording to determine whether DA, at a concentration similar to that detected by FCV, can modulate activity and synaptic transmission/integration. TH- and DA-immunoreactive axons mostly formed symmetric synapses. Because DbetaH-immunoreactive axons were rare and formed asymmetric synapses, they comprised the minority of TH-immunoreactive synapses. Voltammetry demonstrated that DA release was sufficient for the activation of receptors and abolished by blockade of voltage-dependent Na+ channels or removal of extracellular Ca2+. The lifetime and concentration of extracellular DA was increased by blockade of the DA transporter. Dopamine application depolarized STN neurons, increased their frequency of activity and reduced the impact of gamma-aminobutyric acid (GABA)-ergic inputs. These findings suggest that SN DA neurons directly modulate the activity of STN neurons and their loss may contribute to the abnormal activity of STN neurons in PD.

Animals↗

A model of reverse spike frequency adaptation and repetitive firing of subthalamic nucleus neurons.

Subthalamic nucleus neurons exhibit reverse spike-frequency adaptation. This occurs only at firing rates of 20-50 spikes/s and higher. Over this same frequency range, there is an increase in the steady-state frequency-intensity (F-I) curve's slope (the secondary range). Specific blockade of high-voltage activated calcium currents reduced the F-I curve slope and reverse adaptation. Blockade of calcium-dependent potassium current enhanced secondary range firing. A simple model that exhibited these properties used spike-triggered conductances similar to those in subthalamic neurons. It showed: 1) Nonaccumulating spike afterhyperpolarizations produce positively accelerating F-I curves and spike-frequency adaptation that is complete after the second spike. 2) Combinations of accumulating aftercurrents result in a linear F-I curve, whose slope depends on the relative contributions of inward and outward currents. Spike-frequency adaptation can be gradual. 3) With both accumulating and nonaccumulating aftercurrents, primary and secondary ranges will be present in the F-I curve. The slope of the primary range is determined by the nonaccumulating conductance; the accumulating conductances govern the secondary range. The transition is determined by the relative strengths of accumulating and nonaccumulating currents. 4) Spike-threshold accommodation contributes to the secondary range, reducing its slope at high firing rates. Threshold accommodation can stabilize firing when inward aftercurrents exceed outward ones. 5) Steady-state reverse adaptation results when accumulated inward aftercurrents exceed outward ones. This requires spike-threshold accommodation. Transient speedup arises when inward currents are smaller than outward ones at steady state, but accumulate more rapidly. 6) The same mechanisms alter firing in response to irregular patterns of synaptic conductances, as cell excitability fluctuates with changes in firing rate.

Adaptation, Physiological↗

Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nucleus neurons in vitro.

Distinct activity patterns in subthalamic nucleus (STN) neurons are observed during normal voluntary movement and abnormal movement in Parkinson's disease (PD). To determine how such patterns of activity are regulated by small conductance potassium (SK)/calcium-activated potassium (KCa) channels and voltage-gated calcium (Cav) channels, STN neurons were recorded in the perforated patch configuration in slices, [which were prepared from postnatal day 16 (P16)-P30 rats and held at 37 degrees C] and then treated with the SK KCa channel antagonist apamin or the SK KCa channel agonist 1-ethyl-2-benzimidazolinone or the Cav channel antagonists w-omega-conotoxin GVIA (Cav2.2-selective) or nifedipine (Cav1.2-1.3-selective) [corrected]. In other experiments, fura-2 was introduced as an indicator of intracellular calcium dynamics. A component of the current underlying single-spike afterhyperpolarization was sensitive to apamin, phase-locked to calcium entry via Cav2.2 channels, and necessary for precise, autonomous, single-spike oscillation. SK KCa/Cav2.2 channel coupling did not underlie spike-frequency adaptation but limited activity in response to current injection by encoding the accumulation of intracellular calcium, maintained the characteristic sigmoidal frequency-intensity relationship and generated a post-train afterhyperpolarization. In addition, SK KCa channels terminated rebound burst activity more effectively in neurons with short-duration bursts (<100 msec) than neurons with long-duration bursts (>100 msec), presumably through their activation by Cav3 channels. Cav1.2-1.3 channels were not strongly coupled to SK KCa channels and therefore supported secondary range and long-duration rebound burst firing. In summary, SK KCa channels play a fundamental role in autonomous, driven, and rebound activity and oppose the transition from autonomous, rhythmic, single-spike activity to burst firing in STN neurons.

Action Potentials↗

"The little engine that could": voltage-dependent Na(+) channels and the subthalamic nucleus.

The most effective treatment for late-stage Parkinson's disease is to electrically stimulate the subthalamic nucleus (STN) at high frequencies. Why this strategy works is unclear. The work by Do and Bean shows that the Na channels in STN neurons have distinctive features--like resurgence--that regulate their spiking behavior, providing new insights into the mechanism of DBS.

Animals↗

Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network.

Recent anatomical, physiological and computer modeling studies have revealed that oscillatory processes at the levels of single neurons and neuronal networks in the subthalamic nucleus (STN) and external globus pallidus (GPe) are associated with the operation of the basal ganglia in health and in Parkinson's disease (PD). Autonomous oscillation of STN and GPe neurons underlies tonic activity and is important for synaptic integration, whereas abnormal low-frequency rhythmic bursting in the STN and GPe is characteristic of PD. These recent findings provide further support for the view that the basal ganglia use both the pattern and the rate of neuronal activity to encode information.

Animals↗