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BACKGROUND: Adults with Parkinson disease (PD) are hospitalized at higher rates than age-matched controls, and these hospitalizations are associated with significant morbidity. However, little is known about the consequences of critical illness requiring intensive care unit (ICU)-level care in patients with PD. The aim of this study was to define the characteristics and outcomes of adults with PD admitted to the ICU. METHODS: We performed a retrospective nested case-control study using the Medical Information Mart for Intensive Care IV data set. Adults with PD were identified, and the index ICU admission for these subjects was matched 1:4 with index ICU admissions without a PD diagnosis based on age, sex, comorbidities, illness severity, ICU type, and need for mechanical ventilation. Primary outcomes were in-hospital mortality and discharge location. Secondary outcomes were length of stay and prespecified complications. RESULTS: A total of 630 adults with PD were identified. Patients with PD were older and were more likely to be male, have more comorbidities, and have higher illness severity at presentation. A matched analysis revealed adults with PD did not have a significant difference in in-hospital mortality but were more likely to be discharged to a higher level of care. Adults with PD had longer hospital lengths of stay and increased odds of delirium, pressure ulcers, and ileus. CONCLUSIONS: During critical illness, patients with PD are at increased risk for longer hospital lengths of stay and complications and require a higher level of care at discharge than matched controls. These findings reveal targets for interventions to improve outcomes for patients with PD and may inform discussions about goals of care in this population.
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The substantia nigra pars reticulata (SNr), a crucial basal ganglia output nucleus, contains a dense expression of dopamine D1 receptors (D1Rs), along with dendrites belonging to dopaminergic neurons of substantia nigra pars compacta. These D1Rs are primarily located on the terminals of striatonigral medium spiny neurons, suggesting their involvement in the regulation of neurotransmitter release from the direct pathway in response to somatodendritic dopamine release. To explore the hypothesis that D1Rs modulate GABA release from striatonigral synapses, we conducted optical recordings of striatonigral activity and postsynaptic patch-clamp recordings from SNr neurons in the presence of dopamine and D1R agonists. We found that dopamine inhibits optogenetically triggered striatonigral GABA release by modulating vesicle fusion and Ca 2+ influx in striatonigral boutons. Notably, the effect of DA was independent of D1R activity but required activation of 5-HT1B receptors. Our results suggest a serotonergic mechanism involved in the therapeutic actions of dopaminergic medications for Parkinson's disease and psychostimulant-related disorders.
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Autism Spectrum Disorders (ASD) consist of diverse neurodevelopmental conditions where core behavioral symptoms are critical for diagnosis. Altered dopamine neurotransmission in the striatum has been suggested to contribute to the behavioral features of ASD. Here, we examine dopamine neurotransmission in a mouse model of ASD characterized by elevated expression of the eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation, using a comprehensive approach that encompasses genetics, behavior, synaptic physiology, and imaging. The results indicate that increased eIF4E expression leads to behavioral inflexibility and impaired striatal dopamine release. The loss of normal dopamine neurotransmission is due to a defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons. These findings reveal an intricate interplay between eIF4E, DA neurotransmission, and behavioral flexibility, provide a mechanistic understanding of ASD symptoms and offer a foundation for targeted therapeutic interventions.
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INTRODUCTION: During hospital admissions, patients with dementia are at risk for developing delirium, an acute state of brain failure associated with significant morbidity. There are currently no pharmacologic tools to treat or prevent delirium. Decreased cholinergic signaling plays a role in the pathophysiology of both disorders. Whether enhanced pre-hospital cholinergic signaling in patients with dementia improves outcomes during critical illness remains unknown. METHODS: We utilized the Medical Information Mart for Intensive Care III (MIMIC-III) database to determine whether pre-hospital donepezil use was associated with improved outcomes during critical illness in dementia patients. RESULTS: We identified 2734 subjects with dementia admitted to the intensive care unit (ICU; 447 received donepezil). After adjusting for confounders, patients with dementia who were receiving donepezil had a significantly reduced in-hospital and 90-day mortality, ICU length of stay, and duration of mechanical ventilation. Donepezil use was associated with, and its benefit was mediated by, reduced delirium. DISCUSSION: Patients with dementia who are treated with donepezil have improved outcomes during critical illness and reductions in delirium. HIGHLIGHTS: No pharmacologic treatments exist to reduce delirium in patients with dementia. Donepezil improves outcomes during critical illness in patients with dementia. Improved outcomes are mediated by a reduction in hospital delirium. Future studies in patients with dementia should prospectively evaluate donepezil in the prevention of delirium.
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Delírio , Demência , Humanos , Donepezila/uso terapêutico , Estado Terminal/terapia , Colinérgicos/uso terapêutico , Demência/tratamento farmacológicoRESUMO
The most common genetic risk factors for Parkinson's disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes ß-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from postmortem human GBA-PD brains was present on the lysosomal surface and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). MT GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including α-synuclein. Single-cell transcriptional analysis and proteomics of brains from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif rescued primary substantia nigra dopaminergic neurons from MT GCase-induced neuronal death. We conclude that MT GBA1 alleles block CMA function and produce α-synuclein accumulation.
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Autofagia Mediada por Chaperonas , Doença de Parkinson , Animais , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Camundongos , Mutação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , alfa-Sinucleína/genéticaRESUMO
Midbrain dopaminergic (mDA) neurons exhibit extensive dendritic and axonal arborizations, but local protein synthesis is not characterized in these neurons. Here, we investigate messenger RNA (mRNA) localization and translation in mDA neuronal axons and dendrites, both of which release dopamine (DA). Using highly sensitive ribosome-bound RNA sequencing and imaging approaches, we find no evidence for mRNA translation in mDA axons. In contrast, mDA neuronal dendrites in the substantia nigra pars reticulata (SNr) contain ribosomes and mRNAs encoding the major components of DA synthesis, release, and reuptake machinery. Surprisingly, we also observe dendritic localization of mRNAs encoding synaptic vesicle-related proteins, including those involved in exocytic fusion. Our results are consistent with a role for local translation in the regulation of DA release from dendrites, but not from axons. Our translatome data define a molecular signature of sparse mDA neurons in the SNr, including the enrichment of Atp2a3/SERCA3, an atypical ER calcium pump.
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Neurônios Dopaminérgicos/metabolismo , Biossíntese de Proteínas/fisiologia , RNA Mensageiro/metabolismo , Animais , Axônios/metabolismo , Dendritos/metabolismo , Dopamina/metabolismo , Feminino , Masculino , Mesencéfalo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Ribossomos/metabolismo , Análise de Sequência de RNA/métodos , Substância Negra/metabolismoRESUMO
Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical to action selection, motor learning, and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine (DA) neurons; however, little is known about its development. Here, we report that ChI spontaneous activity increases during postnatal development of male and female mice, concomitant with a decreased afterhyperpolarization (AHP). We characterized the postnatal development of four currents that contribute to the spontaneous firing rate of ChIs, including ISK, IA, Ih, and INaP We demonstrated that the developmental increase in INaP drives increased ChI firing rates during the postnatal period and can be reversed by the INaP inhibitor, ranolazine. We next addressed whether immature cholinergic signaling may lead to functional differences in DA release during the juvenile period. In the adult striatum, nicotinic acetylcholine receptors (nAChRs) prevent linear summation of DA release in response to trains of high-frequency stimuli. We show that, in contrast, during the second postnatal week, DA release linearly sums with trains of high-frequency stimuli. Consistently, nAChR antagonists exert little effect on dopamine release at postnatal day (P)10, but enhance the summation of evoked DA release in mice older than postnatal day P28. Together, these results reveal that postnatal maturation of ChI activity is due primarily to enhanced INaP and identify an interaction between developing cholinergic signaling and DA neurotransmission in the juvenile striatum.SIGNIFICANCE STATEMENT Motor skills and motivated behavior develop rapidly in juvenile rodents. Recent work has highlighted processes that contribute to the postnatal maturation of striatal principal neurons during development. The functional development of the striatal cholinergic interneuron (ChI), however, has been unexplored. In this study, we tracked the ontogeny of ChI activity and cellular morphology, as well as the developmental trajectory of specific conductances that contribute to the activity of these cells. We further report a link between cholinergic signaling and dopamine (DA) release, revealing a change in the frequency-dependence of DA release during the early postnatal period that is mediated by cholinergic signaling. This study provides evidence that striatal microcircuits are dynamic during the postnatal period and that they undergo coordinated maturation.
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Envelhecimento/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Interneurônios/fisiologia , Neostriado/crescimento & desenvolvimento , Neostriado/metabolismo , Sistema Nervoso Parassimpático/crescimento & desenvolvimento , Potenciais de Ação/fisiologia , Animais , Dendritos/metabolismo , Dendritos/ultraestrutura , Fenômenos Eletrofisiológicos , Feminino , Canais Iônicos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ranolazina/farmacologia , Receptores Nicotínicos/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
BACKGROUND: Autophagy is intensively studied in cancer, metabolic and neurodegenerative diseases, but little is known about its role in pathological conditions linked to altered neurotransmission. We examined the involvement of autophagy in levodopa (l-dopa)-induced dyskinesia, a frequent motor complication developed in response to standard dopamine replacement therapy in parkinsonian patients. METHODS: We used mouse and non-human primate models of Parkinson's disease to examine changes in autophagy associated with chronic l-dopa administration and to establish a causative link between impaired autophagy and dyskinesia. RESULTS: We found that l-dopa-induced dyskinesia is associated with accumulation of the autophagy-specific substrate p62, a marker of autophagy deficiency. Increased p62 was observed in a subset of projection neurons located in the striatum and depended on l-dopa-mediated activation of dopamine D1 receptors, and mammalian target of rapamycin. Inhibition of mammalian target of rapamycin complex 1 with rapamycin counteracted the impairment of autophagy produced by l-dopa, and reduced dyskinesia. The anti-dyskinetic effect of rapamycin was lost when autophagy was constitutively suppressed in D1 receptor-expressing striatal neurons, through inactivation of the autophagy-related gene protein 7. CONCLUSIONS: These findings indicate that augmented responsiveness at D1 receptors leads to dysregulated autophagy, and results in the emergence of l-dopa-induced dyskinesia. They further suggest the enhancement of autophagy as a therapeutic strategy against dyskinesia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Discinesia Induzida por Medicamentos , Transtornos Parkinsonianos , Animais , Antiparkinsonianos/toxicidade , Autofagia , Corpo Estriado , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/etiologia , Humanos , Levodopa/toxicidade , Camundongos , OxidopaminaRESUMO
Macroautophagy (hereafter referred to as autophagy) plays a critical role in neuronal function related to development and degeneration. Here, we investigated whether autophagy is developmentally regulated in the striatum, a brain region implicated in neurodevelopmental disease. We demonstrate that autophagic flux is suppressed during striatal postnatal development, reaching adult levels around postnatal day 28 (P28). We also find that mTOR signaling, a key regulator of autophagy, increases during the same developmental period. We further show that mTOR signaling is responsible for suppressing autophagy, via regulation of Beclin-1 and VPS34 activity. Finally, we discover that autophagy is downregulated during late striatal postnatal development (P28) in mice with in utero exposure to valproic acid (VPA), an established mouse model of autism spectrum disorder (ASD). VPA-exposed mice also display deficits in striatal neurotransmission and social behavior. Correction of hyperactive mTOR signaling in VPA-exposed mice restores social behavior. These results demonstrate that neurons coopt metabolic signaling cascades to developmentally regulate autophagy and provide additional evidence that mTOR-dependent signaling pathways represent pathogenic signaling cascades in ASD mouse models that are active during specific postnatal windows.
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Macroautophagy/autophagy is implicated in the maintenance of normal neuronal activity through the regulation of synaptic function and plasticity. However, differences in autophagic degradation within different classes of neurons have not been examined. We have recently demonstrated that autophagy plays very different roles in the two closely related principal neurons of the striatum - the spiny projection neurons of the direct (dSPN) and indirect (iSPN) pathways. Behavioral and electrophysiological experiments revealed that the absence of autophagy in either of these SPN pathways produces unique effects on motor learning, dendritic length, and intrinsic excitability. Specifically, autophagy is required for the normal development of synaptic inputs onto dSPNs, while being required for intrinsic excitability in iSPNs. In iSPNs, this occurs through the regulation of the activity of the KCNJ/Kir2 ion channel, and provides a first demonstration of autophagic control of neuronal intrinsic excitability. ABBREVIATIONS: ASD: autism spectrum disorders; dSPNs: direct pathway spiny projection neurons; iSPNs: indirect pathway spiny projection neurons; Kir2: inwardly rectifying potassium channel 2.
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Autofagia , Corpo Estriado , Macroautofagia , Neostriado , NeurôniosRESUMO
The basal ganglia are a group of subcortical nuclei that contribute to action selection and reinforcement learning. The principal neurons of the striatum, spiny projection neurons of the direct (dSPN) and indirect (iSPN) pathways, maintain low intrinsic excitability, requiring convergent excitatory inputs to fire. Here, we examined the role of autophagy in mouse SPN physiology and animal behavior by generating conditional knockouts of Atg7 in either dSPNs or iSPNs. Loss of autophagy in either SPN population led to changes in motor learning but distinct effects on cellular physiology. dSPNs, but not iSPNs, required autophagy for normal dendritic structure and synaptic input. In contrast, iSPNs, but not dSPNs, were intrinsically hyperexcitable due to reduced function of the inwardly rectifying potassium channel, Kir2. These findings define a novel mechanism by which autophagy regulates neuronal activity: control of intrinsic excitability via the regulation of potassium channel function.
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Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Macroautofagia/genética , Macroautofagia/fisiologia , Neurônios/fisiologia , Animais , Autofagia/fisiologia , Gânglios da Base , Comportamento Animal , Feminino , Aprendizagem , Masculino , Camundongos , Camundongos Knockout , Canais de Potássio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Desempenho Psicomotor/fisiologia , Fatores Sexuais , TranscriptomaRESUMO
Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved pathway in which proteins and organelles are delivered to the lysosome for degradation. In neurons, autophagy was originally described as associated with disease states and neuronal survival. Over the last decade, however, evidence has accumulated that autophagy controls synaptic function in both the axon and dendrite. Here, we review this literature, highlighting the role of autophagy in the pre- and postsynapse, synaptic plasticity, and behavior. We end by discussing open questions in the field of synaptic autophagy.
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Autofagia , Doenças Neurodegenerativas/patologia , Plasticidade Neuronal , Neurônios/patologia , Animais , Sobrevivência Celular , HumanosRESUMO
The dendritic protrusions known as spines represent the primary postsynaptic location for excitatory synapses. Dendritic spines are critical for many synaptic functions, and their formation, modification, and turnover are thought to be important for mechanisms of learning and memory. At many excitatory synapses, dendritic spines form during the early postnatal period, and while many spines are likely being formed and removed throughout life, the net number are often gradually "pruned" during adolescence to reach a stable level in the adult. In neurodevelopmental disorders, spine pruning is disrupted, emphasizing the importance of understanding its governing processes. Autophagy, a process through which cytosolic components and organelles are degraded, has recently been shown to control spine pruning in the mouse cortex, but the mechanisms through which autophagy acts remain obscure. Here, we draw on three widely studied prototypical synaptic pruning events to focus on two governing principles of spine pruning: 1) activity-dependent synaptic competition and 2) non-neuronal contributions. We briefly review what is known about autophagy in the central nervous system and its regulation by metabolic kinases. We propose a model in which autophagy in both neurons and non-neuronal cells contributes to spine pruning, and how other processes that regulate spine pruning could intersect with autophagy. We further outline future research directions to address outstanding questions on the role of autophagy in synaptic pruning.
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Autofagia/fisiologia , Sistema Nervoso Central/crescimento & desenvolvimento , Neuroglia/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Sistema Nervoso Central/fisiologia , HumanosRESUMO
Neural circuits are formed and refined during childhood, including via critical changes in neuronal excitability. Here, we investigated the ontogeny of striatal intrinsic excitability. We found that dopamine neurotransmission increases from the first to the third postnatal week in mice and precedes the reduction in spiny projection neuron (SPN) intrinsic excitability during the fourth postnatal week. In mice developmentally deficient for striatal dopamine, direct pathway D1-SPNs failed to undergo maturation of excitability past P18 and maintained hyperexcitability into adulthood. We found that the absence of D1-SPN maturation was due to altered phosphatidylinositol 4,5-biphosphate dynamics and a consequent lack of normal ontogenetic increases in Kir2 currents. Dopamine replacement corrected these deficits in SPN excitability when provided from birth or during a specific period of juvenile development (P18-P28), but not during adulthood. These results identify a sensitive period of dopamine-dependent striatal maturation, with implications for the pathophysiology and treatment of neurodevelopmental disorders.
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Corpo Estriado/crescimento & desenvolvimento , Período Crítico Psicológico , Dopamina/farmacologia , Neurônios/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Distribuição AleatóriaRESUMO
Several lines of evidence place alpha-synuclein (aSyn) at the center of Parkinson's disease (PD) etiology, but it is still unclear why overexpression or mutated forms of this protein affect some neuronal populations more than others. Susceptible neuronal populations in PD, dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the locus coeruleus (LC), are distinguished by relatively high cytoplasmic concentrations of dopamine and calcium ions. Here we review the evidence for the multi-hit hypothesis of neurodegeneration, including recent papers that demonstrate synergistic interactions between aSyn, calcium ions and dopamine that may lead to imbalanced protein turnover and selective susceptibility of these neurons. We conclude that decreasing the levels of any one of these toxicity mediators can be beneficial for the survival of SNpc and LC neurons, providing multiple opportunities for targeted drug interventions aimed at modifying the course of PD.
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l-DOPA provides highly effective treatment for Parkinson's disease, but l-DOPA induced dyskinesia (LID) is a very debilitating response that eventually is presented by a majority of patients. A central issue in understanding the basis of LID is whether it is due to a response to chronic l-DOPA over years of therapy, and/or due to synaptic changes that follow the loss of dopaminergic neurotransmission and then triggered by acute l-DOPA administration. We review recent work that suggests that specific synaptic changes in the D1 dopamine receptor-expressing direct pathway striatal projection neurons due to loss of dopamine in Parkinson's disease are responsible for LID. Chronic l-DOPA may nevertheless modulate LID through priming mechanisms.
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Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/patologia , Levodopa/efeitos adversos , Plasticidade Neuronal/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológicoRESUMO
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+). We demonstrate that the higher level of neurotoxicity in SN than VTA neurons was due to SN neuron-specific toxin-induced increase in cytosolic dopamine (DA) and Ca2+, followed by an elevation of mitochondrial Ca2+, activation of nitric oxide synthase (NOS), and mitochondrial oxidation. The increase in cytosolic Ca2+ was not caused by MPP+-induced oxidative stress, but rather depended on the activity of both L-type calcium channels and aSyn expression, suggesting that these two established pathogenic factors in PD act in concert.
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1-Metil-4-fenilpiridínio/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Área Tegmentar Ventral/metabolismo , alfa-Sinucleína/metabolismo , Animais , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Neurônios Dopaminérgicos/metabolismo , CamundongosRESUMO
Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.