Joshua A. Goldberg

Thalamic Gating of Corticostriatal Signaling by Cholinergic Interneurons

Salient stimuli redirect attention and suppress ongoing motor activity. This attentional shift is thought to rely upon thalamic signals to the striatum to shift cortically driven action selection, but the network mechanisms underlying this interaction are unclear. Using a brain slice preparation that preserved cortico- and thalamostriatal connectivity, it was found that activation of thalamostriatal axons in a way that mimicked the response to salient stimuli induced a burst of spikes in striatal cholinergic interneurons that was followed by a pause lasting more than half a second. This patterned interneuron activity triggered a transient, presynaptic suppression of cortical input to both major classes of principal medium spiny neuron (MSN) that gave way to a prolonged enhancement of postsynaptic responsiveness in striatopallidal MSNs controlling motor suppression. This differential regulation of the corticostriatal circuitry provides a neural substrate for attentional shifts and cessation of ongoing motor activity with the appearance of salient environmental stimuli.

Neuronal oscillations in the basal ganglia and movement disorders: evidence from whole animal and human recordings.

Neuronal oscillations underlie a number of physiological processes, such as respiration, diurnal rhythms of the sleep-wake cycle, and gait. Oscillatory activity can be observed in many different brain regions and can be synchronized across these different regions or nuclei. Oscillatory activity has

RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion.

Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D2 dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion, D2 dopamine receptor modulation of calcium (Ca2+) channels controlling vesicular acetylcholine release in interneurons was unchanged, but M4 muscarinic autoreceptor coupling to these same channels was markedly attenuated. This adaptation was attributable to the upregulation of RGS4—an autoreceptor-associated, GTPase-accelerating protein. This specific signaling adaptation extended to a broader loss of autoreceptor control of interneuron spiking. These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease.

Spike Synchronization in the Cortex-Basal Ganglia Networks of Parkinsonian Primates Reflects Global Dynamics of the Local Field Potentials

Cortical local field potentials (LFPs) reflect synaptic potentials and accordingly correlate with neuronal discharge. Because LFPs are coherent across substantial cortical areas, we hypothesized that cortical spike correlations could be predicted from them. Because LFPs recorded in the basal ganglia (BG) are also correlated with neuronal discharge and are clinically accessible in Parkinsons disease patients, we were interested in testing this hypothesis in the BG, as well. We recorded LFPs and unit discharge from multiple electrodes, which were placed in primary motor cortex or in the basal ganglia (striatum and pallidum) of two monkeys before and after rendering them parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We used the method of partial spectra to construct LFP predictors of the spike cross-correlation functions (CCFs). The predicted CCF is an estimate of the correlation between two neurons under the assumption that their association is explained solely by the association of each with the LFP recorded on a third electrode. In the normal condition, the predictors account for cortical rate covariations but not for the association among the tonically active neurons of the striatum. In the parkinsonian condition, with the appearance of 10 Hz oscillations throughout the cortex-basal ganglia networks, the LFP predictors account remarkably better for the CCFs in both the cortex and the basal ganglia. We propose that, in the parkinsonian condition, the cortex-basal ganglia networks are more tightly related to global modes of brain dynamics that are echoed in the LFP.

Control of spontaneous firing patterns by the selective coupling of calcium currents to calcium-activated potassium currents in striatal cholinergic interneurons.

The spontaneous firing patterns of striatal cholinergic interneurons are sculpted by potassium currents that give rise to prominent afterhyperpolarizations (AHPs). Large-conductance calcium-activated potassium (BK) channel currents contribute to action potential (AP) repolarization; small-conductance calcium-activated potassium channel currents generate an apamin-sensitive medium AHP (mAHP) after each AP; and bursts of APs generate long-lasting slow AHPs (sAHPs) attributable to apamin-insensitive currents. Because all these currents are calcium dependent, we conducted voltage- and current-clamp whole-cell recordings while pharmacologically manipulating calcium channels of the plasma membrane and intracellular stores to determine what sources of calcium activate the currents underlying AP repolarization and the AHPs. The Cav2.2 (N-type) blocker ω-conotoxin GVIA (1 μm) was the only blocker that significantly reduced the mAHP, and it induced a transition to rhythmic bursting in one-third of the cells tested. Cav1 (L-type) blockers (10 μm dihydropyridines) were the only ones that significantly reduced the sAHP. When applied to cells induced to burst with apamin, dihydropyridines reduced the sAHPs and abolished bursting. Depletion of intracellular stores with 10 mm caffeine also significantly reduced the sAHP current and reversibly regularized firing. Application of 1 μm ω-conotoxin MVIIC (a Cav2.1/2.2 blocker) broadened APs but had a negligible effect on APs in cells in which BK channels were already blocked by submillimolar tetraethylammonium chloride, indicating that Cav2.1 (Q-type) channels provide the calcium to activate BK channels that repolarize the AP. Thus, calcium currents are selectively coupled to the calcium-dependent potassium currents underlying the AHPs, thereby creating mechanisms for control of the spontaneous firing patterns of these neurons.

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Parkinsons disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cell-specific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.

Dopamine Replacement Therapy Does Not Restore the Full Spectrum of Normal Pallidal Activity in the 1-Methyl-4-Phenyl-1,2,3,6-Tetra-Hydropyridine Primate Model of Parkinsonism

Current physiological studies emphasize the role of neuronal oscillations and synchronization in the pathophysiology of Parkinson’s disease; however, little is known about their specific roles in the neuronal substrate of dopamine replacement therapy (DRT). We investigated oscillatory activity and correlations throughout the different states of levodopa-naive parkinsonism as well as “Off–On” and dyskinetic states of DRT in the external globus pallidum (GPe) of tremulous (vervet) and rigid-akinetic (macaque) monkeys and in the internal globus pallidum (GPi) of the vervet monkey. We found that, although oscillatory activity of cells and interneuronal correlation in both pallidal segments increases after induction of parkinsonism with 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) and decreases in response to DRT, important differences exist between the two pallidal segments. In the GPi, the fraction of oscillatory cells and relative power of oscillations were significantly higher than in the GPe, and the dominant frequency was within the range of 7.5–13.5 Hz compared with a range of 4.5–7.5 Hz within the GPe. The interneuronal correlations were mostly oscillatory in the GPi, whereas at least half are non-oscillatory in the GPe. We demonstrate that the tremor characteristics after exposure to DRT do not resemble those of the normal or the levodopa-naive state. Moreover, although DRT reverses the MPTP-induced neuronal changes (rate, pattern, and pairwise correlations), the balance between GPe and GPi fails to restore. We therefore suggest that this imbalance reflects additional abnormal organization of the basal ganglia networks in response to dopamine replacement and may constitute the physiological substrate of the limitations and side effects of chronic DRT.

Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease

Mitochondrial oxidant stress is widely viewed as being critical to pathogenesis in Parkinsons disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity. To test this hypothesis, we characterized neurons in the dorsal motor nucleus of the vagus (DMV), a population of cholinergic neurons that show signs of pathology in the early stages of Parkinsons disease, in mouse brain slices. DMV neurons were slow, autonomous pacemakers with broad spikes, leading to calcium entry that was weakly buffered. Using a transgenic mouse expressing a redox-sensitive optical probe targeted to the mitochondrial matrix, we found that calcium entry during pacemaking created a basal mitochondrial oxidant stress. Knocking out DJ-1 (also known as PARK7), a gene associated with early-onset Parkinsons disease, exacerbated this stress. These results point to a common mechanism underlying mitochondrial oxidant stress in Parkinsons disease and a therapeutic strategy to ameliorate it.

Oscillations in the Basal Ganglia: The good, the bad, and the unexpected

Oscillations are present at many levels in the basal ganglia (BG), and can describe regular fluctuations in, for example, gene expression, current flow across the plasma membrane, the firing rate of a single neuron, the activity within and between small networks of neurons, and activity at the level of whole nuclei. Many BG neurons, including those of the subthalamic nucleus, globus pallidus (both segments), substantia nigra (both divisions), and some striatal interneurons, are endowed with a battery of intrinsic membrane properties that promote the expression of oscillatory discharge at both ‘rest’ (or in functional isolation) and in response to organized synaptic input (Richards et al., 1997; Bennett and Wilson, 1999; Bevan et al., 2002). The oscillatory activity of a single cell may or may not be synchronized with the oscillatory activity of another cell or network of cells. Indeed, oscillation and synchronization are distinct properties of neuronal networks. This is well illustrated in the BG; while the firing patterns of pallidal neurons are strongly periodic, the discharges of pairs of these neurons are typically uncorrelated (Bergman et al., 1998; Boraud et al., 2002). Conversely, the activity of BG neurons may be synchronized to within milliseconds but without being strongly periodic. These facts aside, it may be that synchronized oscillations offer the BG, and indeed the whole brain, something more than the simple sum of the parts (Steriade, 2000; Engel et al., 2001; Buzsaki and Draguhn, 2004). For example, they may provide the brain with a mechanism to execute tasks that require the combined function of distant and disparate

Muscarinic Modulation of Striatal Function and Circuitry

Striatal cholinergic interneurons are pivotal modulators of the striatal circuitry involved in action selection and decision making. Although nicotinic receptors are important transducers of acetylcholine release in the striatum, muscarinic receptors are more pervasive and have been more thoroughly studied. In this review, the effects of muscarinic receptor signaling on the principal cell types in the striatum and its canonical circuits will be discussed, highlighting new insights into their role in synaptic integration and plasticity. These studies, and those that have identified new circuit elements driven by activation of nicotinic receptors, make it clear that temporally patterned activity in cholinergic interneurons must play an important role in determining the effects on striatal circuitry. These effects could be critical to the response to salient environmental stimuli that serve to direct behavior.