Cholinergic deficits selectively boost cortical intratelencephalic control of striatum in male Huntington's disease model mice.

Huntington's disease (HD) is a progressive, neurodegenerative disease caused by a CAG triplet expansion in huntingtin. Although corticostriatal dysfunction has long been implicated in HD, the determinants and pathway specificity of this pathophysiology are not fully understood. Here, using a male zQ175 knock-in mouse model of HD we carry out optogenetic interrogation of intratelencephalic and pyramidal tract synapses with principal striatal spiny projection neurons (SPNs).

Ca channels couple spiking to mitochondrial metabolism in substantia nigra dopaminergic neurons.

How do neurons match generation of adenosine triphosphate by mitochondria to the bioenergetic demands of regenerative activity? Although the subject of speculation, this coupling is still poorly understood, particularly in neurons that are tonically active. To help fill this gap, pacemaking substantia nigra dopaminergic neurons were studied using a combination of optical, electrophysiological, and molecular approaches. In these neurons, spike-activated calcium (Ca) entry through Ca1 channels triggered Ca release from the endoplasmic reticulum, which stimulated mitochondrial oxidative phosphorylation through two complementary Ca-dependent mechanisms: one mediated by the mitochondrial uniporter and another by the malate-aspartate shuttle.

Locus coeruleus anchors a trisynaptic circuit controlling fear-induced suppression of feeding.

The circuit mechanisms underlying fear-induced suppression of feeding are poorly understood. To help fill this gap, mice were fear conditioned, and the resulting changes in synaptic connectivity among the locus coeruleus (LC), the parabrachial nucleus (PBN), and the central nucleus of amygdala (CeA)-all of which are implicated in fear and feeding-were studied. LC neurons co-released noradrenaline and glutamate to excite PBN neurons and suppress feeding.

A Single Amino Acid Determines the Selectivity and Efficacy of Selective Negative Allosteric Modulators of Ca1.3 L-Type Calcium Channels.

Ca channels with a Ca1.3 pore-forming α subunit have been implicated in both neurodegenerative and neuropsychiatric disorders, motivating the development of selective and potent inhibitors of Ca1.3 versus Ca1.

Author Correction: Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain.

Monoamine oxidase (MAO) metabolizes cytosolic dopamine (DA), thereby limiting auto-oxidation, but is also thought to generate cytosolic hydrogen peroxide (HO). We show that MAO metabolism of DA does not increase cytosolic HO but leads to mitochondrial electron transport chain (ETC) activity. This is dependent upon MAO anchoring to the outer mitochondrial membrane and shuttling electrons through the intermembrane space to support the bioenergetic demands of phasic DA release.

Maladaptive Downregulation of Autonomous Subthalamic Nucleus Activity following the Loss of Midbrain Dopamine Neurons.

Abnormal subthalamic nucleus (STN) activity is linked to impaired movement in Parkinson's disease (PD). The autonomous firing of STN neurons, which contributes to their tonic excitation of the extrastriatal basal ganglia and shapes their integration of synaptic input, is downregulated in PD models. Using electrophysiological, chemogenetic, genetic, and optical approaches, we find that chemogenetic activation of indirect pathway striatopallidal neurons downregulates intrinsic STN activity in normal mice but this effect is occluded in Parkinsonian mice.

Mutant huntingtin enhances activation of dendritic Kv4 K channels in striatal spiny projection neurons.

Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits.

Cholinergic Interneurons Amplify Thalamostriatal Excitation of Striatal Indirect Pathway Neurons in Parkinson's Disease Models.

The motor symptoms of Parkinson's disease (PD) are thought to stem from an imbalance in the activity of striatal direct- and indirect-pathway spiny projection neurons (SPNs). Disease-induced alterations in the activity of networks controlling SPNs could contribute to this imbalance. One of these networks is anchored by the parafascicular nucleus (PFn) of the thalamus.

Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress.

The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson's disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients.

α-Synuclein-Dependent Calcium Entry Underlies Differential Sensitivity of Cultured SN and VTA Dopaminergic Neurons to a Parkinsonian Neurotoxin.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra (SN). Although mitochondrial dysfunction and dysregulated α-synuclein (aSyn) expression are postulated to play a role in PD pathogenesis, it is still debated why neurons of the SN are targeted while neighboring dopaminergic neurons of the ventral tegmental area (VTA) are spared. Using electrochemical and imaging approaches, we investigated metabolic changes in cultured primary mouse midbrain dopaminergic neurons exposed to a parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP).

The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain.

We examined adaptations in nucleus accumbens (NAc) neurons in mouse and rat peripheral nerve injury models of neuropathic pain. Injury selectively increased excitability of NAc shell indirect pathway spiny projection neurons (iSPNs) and altered their synaptic connectivity. Moreover, injury-induced tactile allodynia was reversed by inhibiting and exacerbated by exciting iSPNs, indicating that they not only participated in the central representation of pain, but gated activity in ascending nociceptive pathways.

Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The debilitating choreic movements that plague HD patients have been attributed to striatal degeneration induced by the loss of cortically supplied brain-derived neurotrophic factor (BDNF). Here, we show that in mouse models of early symptomatic HD, BDNF delivery to the striatum and its activation of tyrosine-related kinase B (TrkB) receptors were normal.

Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase.

Loss of noradrenergic locus coeruleus (LC) neurons is a prominent feature of aging-related neurodegenerative diseases, such as Parkinson's disease (PD). The basis of this vulnerability is not understood. To explore possible physiological determinants, we studied LC neurons using electrophysiological and optical approaches in ex vivo mouse brain slices.

Sirtuin 3 deficiency does not augment hypoxia-induced pulmonary hypertension.

Alveolar hypoxia elicits increases in mitochondrial reactive oxygen species (ROS) signaling in pulmonary arterial (PA) smooth muscle cells (PASMCs), triggering hypoxic pulmonary vasoconstriction. Mice deficient in sirtuin (Sirt) 3, a nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase, demonstrate enhanced left ventricular hypertrophy after aortic banding, whereas cells from these mice reportedly exhibit augmented hypoxia-induced ROS signaling and hypoxia-inducible factor (HIF)-1 activation. We therefore tested whether deletion of Sirt3 would augment hypoxia-induced ROS signaling in PASMCs, thereby exacerbating the development of pulmonary hypertension (PH) and right ventricular hypertrophy.

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 Parkinson's disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity.

Mitochondrial oxidant stress triggers cell death in simulated ischemia-reperfusion.

To clarify the relationship between reactive oxygen species (ROS) and cell death during ischemia-reperfusion (I/R), we studied cell death mechanisms in a cellular model of I/R. Oxidant stress during simulated ischemia was detected in the mitochondrial matrix using mito-roGFP, a ratiometric redox sensor, and by Mito-Sox Red oxidation. Reperfusion-induced death was attenuated by over-expression of Mn-superoxide dismutase (Mn-SOD) or mitochondrial phospholipid hydroperoxide glutathione peroxidase (mito-PHGPx), but not by catalase, mitochondria-targeted catalase, or Cu,Zn-SOD.

Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1.

Parkinson's disease is a pervasive, ageing-related neurodegenerative disease the cardinal motor symptoms of which reflect the loss of a small group of neurons, the dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial oxidant stress is widely viewed as being responsible for this loss, but why these particular neurons should be stressed is a mystery. Here we show, using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, that the engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons.

Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis.

Low levels of reactive oxygen species (ROS) can function as redox-active signaling messengers, whereas high levels of ROS induce cellular damage. Menadione generates ROS through redox cycling, and high concentrations trigger cell death. Previous work suggests that menadione triggers cytochrome c release from mitochondria, whereas other studies implicate the activation of the mitochondrial permeability transition pore as the mediator of cell death.

Laminar shear stress differentially modulates gene expression of p120 catenin, Kaiso transcription factor, and vascular endothelial cadherin in human coronary artery endothelial cells.

We demonstrated previously that laminar shear stress (LSS) enhances human coronary artery endothelial cell (HCAEC) wound closure via a vascular endothelial cadherin (VE-cadherin)-dependent mechanism. VE-cadherin can interact with p120 catenin (p120(ctn)) to mediate cell locomotion and proliferation. In this study, we hypothesized that p120(ctn) and an interacting protein, Kaiso, a transcriptional factor with which p120(ctn) may interact, would be expressed differentially at the wound border and away from the wound border in HCAEC exposed to LSS.