scholarly journals Dysfunction of cAMP-PKA-calcium signaling axis in striatal medium spiny neurons: a role in schizophrenia and Huntington’s disease pathogenesis

2021 ◽  
Author(s):  
Marija Fjodorova ◽  
Zoe Noakes ◽  
Daniel C. De La Fuente ◽  
Adam C. Errington ◽  
Meng Li
Keyword(s):  
Huntington's Disease ◽  
Calcium Signaling ◽  
Huntington’S Disease ◽  
Cortical Neurons ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Direct Role ◽  
Spiny Neurons ◽  
Signaling Axis

SummaryBackgroundStriatal medium spiny neurons (MSNs) are preferentially lost in Huntington’s disease. Genomic studies also implicate a direct role for MSNs in schizophrenia, a psychiatric disorder known to involve cortical neuron dysfunction. It remains unknown whether the two diseases share similar MSN pathogenesis or if neuronal deficits can be attributed to cell type-dependent biological pathways. Transcription factor BCL11B, which is expressed by all MSNs and deep layer cortical neurons, was recently proposed to drive selective neurodegeneration in Huntington’s disease and identified as a candidate risk gene in schizophrenia.MethodsUsing human stem cell-derived neurons lacking BCL11B as a model, we investigated cellular pathology in MSNs and cortical neurons in the context of these disorders. Integrative analyses between differentially expressed transcripts and published GWAS datasets identified cell type-specific disease-related phenotypes.ResultsWe uncover a role for BCL11B in calcium homeostasis in both neuronal types, while deficits in mitochondrial function and protein kinase A (PKA)-dependent calcium transients are detected only in MSNs. Moreover, BCL11B-deficient MSNs display abnormal responses to glutamate and fail to integrate dopaminergic and glutamatergic stimulation, a key feature of striatal neurons in vivo. Gene enrichment analysis reveals overrepresentation of disorder risk genes among BCL11B-regulated pathways, primarily relating to cAMP-PKA-calcium signaling axis and synaptic signaling.ConclusionsOur study indicates that Huntington’s disease and schizophrenia are likely to share neuronal pathogenesis where dysregulation of intracellular calcium levels is found in both striatal and cortical neurons. In contrast, reduction in PKA signaling and abnormal dopamine/glutamate receptor signaling is largely specific to MSNs.

scholarly journals The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kim Le Cann ◽  
Alec Foerster ◽  
Corinna Rösseler ◽  
Andelain Erickson ◽  
Petra Hautvast ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Induced Pluripotent Stem Cell ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Large Variability ◽  
Spiny Neurons ◽  
Induced Pluripotent

AbstractHuntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.

scholarly journals Striatal Neurodegeneration that Mimics Huntington’s Disease Modifies GABA-induced Currents

2018 ◽  
Vol 8 (12) ◽  
pp. 217
Author(s):  
Jorge Flores-Hernández ◽  
Jeanette Garzón-Vázquez ◽  
Gustavo Hernández-Carballo ◽  
Elizabeth Nieto-Mendoza ◽  
Evelyn Ruíz-Luna ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtype ◽  
Medium Spiny Neurons ◽  
Nitropropionic Acid ◽  
Spiny Neurons ◽  
Excitotoxic Damage ◽  
Induced Currents

Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

Electrophysiological and Morphological Changes in Striatal Spiny Neurons in R6/2 Huntington's Disease Transgenic Mice

2001 ◽  
Vol 86 (6) ◽  
pp. 2667-2677 ◽  
Author(s):  
Gloria J. Klapstein ◽  
Robin S. Fisher ◽  
Hadi Zanjani ◽  
Carlos Cepeda ◽  
Eve S. Jokel ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Action Potentials ◽  
Morphological Changes ◽  
Brain Slices ◽  
Cag Repeats ◽  
Membrane Properties ◽  
Striatal Neurons ◽  
Spiny Neurons ◽  
Active Membrane

We examined passive and active membrane properties and synaptic responses of medium-sized spiny striatal neurons in brain slices from presymptomatic (∼40 days of age) and symptomatic (∼90 days of age) R6/2 transgenics, a mouse model of Huntington's disease (HD) and their age-matched wild-type (WT) controls. This transgenic expresses exon 1 of the human HD gene with ∼150 CAG repeats and displays a progressive behavioral phenotype associated with numerous neuronal alterations. Intracellular recordings were obtained using standard techniques from R6/2 and age-matched WT mice. Few electrophysiological changes occurred in striatal neurons from presymptomatic R6/2 mice. The changes in this age group were increased neuronal input resistance and lower stimulus intensity to evoke action potentials (rheobase). Symptomatic R6/2 mice exhibited numerous electrophysiological alterations, including depolarized resting membrane potentials, increased input resistances, decreased membrane time constants, and alterations in action potentials. Increased stimulus intensities were required to evoke excitatory postsynaptic potentials (EPSPs) in neurons from symptomatic R6/2 transgenics. These EPSPs had slower rise times and did not decay back to baseline by 45 ms, suggesting a more prominent component mediated by activation of N-methyl-d-aspartate receptors. Neurons from both pre- and symptomatic R6/2 mice exhibited reduced paired-pulse facilitation. Data from biocytin-filled or Golgi-impregnated neurons demonstrated decreased dendritic spine densities, smaller diameters of dendritic shafts, and smaller dendritic fields in symptomatic R6/2 mice. Taken together, these findings indicate that passive and active membrane and synaptic properties of medium-sized spiny neurons are altered in the R6/2 transgenic. These physiological and morphological alterations will affect communication in the basal ganglia circuitry. Furthermore, they suggest areas to target for pharmacotherapies to alleviate and reduce the symptoms of HD.

scholarly journals BACHD Mice Recapitulate the Striatal Parvalbuminergic Interneuron Loss Found in Huntington’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Vyshnavi Rallapalle ◽  
Annesha C. King ◽  
Michelle Gray
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Population ◽  
Medium Spiny Neurons ◽  
Cholinergic Interneurons ◽  
Spiny Neurons ◽  
Parvalbumin Interneurons ◽  
Area And Perimeter ◽  
Old Mice ◽  
Disease Grade

Huntington’s disease (HD) is a dominantly inherited, adult-onset neurodegenerative disease characterized by motor, psychiatric, and cognitive abnormalities. Neurodegeneration is prominently observed in the striatum where GABAergic medium spiny neurons (MSN) are the most affected neuronal population. Interestingly, recent reports of pathological changes in HD patient striatal tissue have identified a significant reduction in the number of parvalbumin-expressing interneurons which becomes more robust in tissues of higher disease grade. Analysis of other interneuron populations, including somatostatin, calretinin, and cholinergic, did not reveal significant neurodegeneration. Electrophysiological experiments in BACHD mice have identified significant changes in the properties of parvalbumin and somatostatin expressing interneurons in the striatum. Furthermore, their interactions with MSNs are altered as the mHTT expressing mouse models age with increased input onto MSNs from striatal somatostatin and parvalbumin-expressing neurons. In order to determine whether BACHD mice recapitulate the alterations in striatal interneuron number as observed in HD patients, we analyzed the number of striatal parvalbumin, somatostatin, calretinin, and choline acetyltransferase positive cells in symptomatic 12–14 month-old mice by immunofluorescent labeling. We observed a significant decrease in the number of parvalbumin-expressing interneurons as well as a decrease in the area and perimeter of these cells. No significant changes were observed for somatostatin, calretinin, or cholinergic interneuron numbers while a significant decrease was observed for the area of cholinergic interneurons. Thus, the BACHD mice recapitulate the degenerative phenotype observed in the parvalbumin interneurons in HD patient striata without affecting the number of other interneuron populations in the striatum.

scholarly journals Levodopa-Induced Dyskinesia Is Related to Indirect Pathway Medium Spiny Neuron Excitotoxicity: A Hypothesis Based on an Unexpected Finding

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Svetlana A. Ivanova ◽  
Anton J. M. Loonen
Keyword(s):  
Oxidative Stress ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Medium Spiny Neuron ◽  
Synaptic Membrane ◽  
Medium Spiny Neurons ◽  
Unexpected Finding ◽  
Indirect Pathway ◽  
Spiny Neurons

A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington’s disease. Huntington’s disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson’s disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.

Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington's disease

2016 ◽  
Vol 86 ◽  
pp. 131-139 ◽  
Author(s):  
Anne B. Rocher ◽  
Paolo Gubellini ◽  
Nicolas Merienne ◽  
Lydie Boussicault ◽  
Fanny Petit ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Scaling Up ◽  
Medium Spiny Neurons ◽  
Synaptic Scaling ◽  
Progression Model ◽  
Spiny Neurons ◽  
Slow Progression

scholarly journals TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease

2016 ◽  
Vol 113 (38) ◽  
pp. E5655-E5664 ◽  
Author(s):  
Xiaobei Zhao ◽  
Xu-Qiao Chen ◽  
Eugene Han ◽  
Yue Hu ◽  
Paul Paik ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cortical Neurons ◽  
Striatal Neurons ◽  
Anterograde Transport ◽  
T Complex ◽  
Ring Complex ◽  
Microfluidic Chambers ◽  
Tyrosine Receptor Kinase ◽  
Corticostriatal Circuit

Corticostriatal atrophy is a cardinal manifestation of Huntington’s disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons.

scholarly journals Dysregulated Information Processing by Medium Spiny Neurons in Striatum of Freely Behaving Mouse Models of Huntington's Disease

2008 ◽  
Vol 100 (4) ◽  
pp. 2205-2216 ◽  
Author(s):  
Benjamin R. Miller ◽  
Adam G. Walker ◽  
Anand S. Shah ◽  
Scott J. Barton ◽  
George V. Rebec
Keyword(s):  
Information Processing ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Population Level ◽  
Medium Spiny Neurons ◽  
Processing Scheme ◽  
Background Strain ◽  
Spiny Neurons ◽  
Freely Behaving

Huntington's disease (HD) is an autosomal dominant condition that compromises behavioral output. Dysfunction of medium spiny neurons (MSNs), which are the sole output system of the striatum, is thought to underlie HD pathophysiology. What is not known is how HD alters MSN information processing during behavior, which likely drives the HD behavioral phenotype. We recorded from populations of MSNs in two freely behaving and symptomatic HD mouse models: R6/2 transgenics are based on a C57BL/6J*CBA/J background and show robust behavioral symptoms, whereas knock-in (KI) mice have a 129sv background and express relatively mild behavioral signs. At the single-unit level, we found that the MSN firing rate was elevated in R6/2 but not in KI mice compared with their respective wild-type (WT) controls. In contrast, burst activity, which corresponds to periods of high-frequency firing, was altered in both HD models compared with WT. At the population level, we found that correlated firing between pairs of MSNs was a prominent feature in WT that was reduced in both HD models. Similarly, coincident bursts, which are bursts between pairs of neurons that overlap in time and occur more often in pairs of MSNs that exhibit correlated firing, were decreased in HD mice. Our results indicate an important role in both bursting and correlated burst firing for information processing in MSNs. Dysregulation of this processing scheme, moreover, is a key component of HD pathophysiology regardless of the severity of HD symptoms, genetic construct, and background strain of the mouse models.

scholarly journals Transcriptional Diversity of Medium Spiny Neurons in the Primate Striatum

2020 ◽  
Author(s):  
Jing He ◽  
Michael Kleyman ◽  
Jianjiao Chen ◽  
Aydin Alikaya ◽  
Kathryn M. Rothenhoefer ◽  
...  
Keyword(s):  
Dorsal Striatum ◽  
Cell Types ◽  
Specific Information ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Indirect Pathway ◽  
Spiny Neurons ◽  
Single Nucleus ◽  
Cell Type Specific

AbstractThe striatum is the neural interface between dopamine reward signals and cortico-basal ganglia circuits responsible for value assignments, decisions, and actions. Medium spiny neurons (MSNs) make up the vast majority of striatal neurons and are traditionally classified as two distinct types: direct- and indirect-pathway MSNs. The direct- and indirect-pathway model has been useful for understanding some aspects of striatal functions, but it accounts for neither the anatomical heterogeneity, nor the functional diversity of the striatum. Here, we use single nucleus RNA-sequencing and Fluorescent In-Situ Hybridization to explore MSN diversity in the Rhesus macaque striatum. We identified MSN subtypes that correspond to the major subdivisions of the striatum. These include dorsal striatum subtypes associated with striosome and matrix compartments, as well as ventral striatum subtypes associated with the shell of the nucleus accumbens. We also describe a cell type that is anatomically restricted to “Neurochemically Unique Domains in the Accumbens and Putamen (NUDAPs)”. Together, these results help to advance nonhuman primate studies into the genomics era. The identified cell types provide a comprehensive blueprint for investigating cell type-specific information processing, and the differentially expressed genes lay a foundation for achieving cell type-specific transgenesis in the primate striatum.

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