Striatal compartmentalization and clustering of different subtypes of astrocytes is altered in the zQ175 Huntington′s disease mouse model

Huntington′s disease (HD) is a devastating neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Dysfunction and loss of medium spiny neurons of the striatum is accompanied by astrogliosis (increased astrocyte density and pathology). For decades, astrocytes were considered a homogeneous cell type, but recent transcriptomic analyses revealed astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Here, we studied whether three different striatal astrocyte subtypes expressing glutamine synthetase (GS), glial fibrillary acidic protein (GFAP), or S100 calcium-binding protein B (S100B) are differentially altered in HD. We conducted a comparative immunofluorescence analysis in the striatum of WT and the heterozygous zQ175 HD mouse model and found that the expression and abundance of GFAP+ and S100B+ astrocytes increased in zQ175 mice, while GS+ astrocytes showed no alteration. We then explored whether there was a differential spatial distribution of any of these subtypes within the striatum. We developed a systematic brain compartmentalization approach and found that while GS+ and S100B+ astrocytes were more homogeneously distributed throughout the striatum in zQ175 mice, GFAP+ astrocytes preferentially accumulated in the dorsomedial and dorsolateral striatum, which are regions associated with goal-directed and habitual behaviors. Additionally, GFAP+ astrocytes in zQ175 mice showed increased clustering, a parameter that indicates increased proximity and that is associated with localized inflammation and/or neurodegeneration. Our data suggest a differential susceptibility in both increased density and striatal compartmentalization of different subtypes of astrocytes in zQ175. These results highlight new potential implications for our understanding of astrocyte pathology in HD.

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Sex-specific involvement of indirect-pathway medium spiny neurons in behavioral alteration of 16p11.2 hemi-deletion mouse model

IBRO Reports ◽

10.1016/j.ibror.2019.07.1549 ◽

2019 ◽

Vol 6 ◽

pp. S494

Author(s):

Jaekyoon Kim ◽

Christopher Angelakos ◽

Joseph Linch ◽

Sarah Ferri ◽

Ted Abel

Keyword(s):

Mouse Model ◽

Medium Spiny Neurons ◽

Indirect Pathway ◽

Behavioral Alteration ◽

Spiny Neurons

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Biology and Bias in Cell Type-Specific RNAseq of Nucleus Accumbens Medium Spiny Neurons

Scientific Reports ◽

10.1038/s41598-019-44798-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Hope Kronman ◽

Felix Richter ◽

Benoit Labonté ◽

Ramesh Chandra ◽

Shan Zhao ◽

...

Keyword(s):

Nucleus Accumbens ◽

Medium Spiny Neurons ◽

Cell Type ◽

Spiny Neurons ◽

Cell Type Specific

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

10.1101/2021.10.08.463614 ◽

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.

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Unique Properties of R-Type Calcium Currents in Neocortical and Neostriatal Neurons

Journal of Neurophysiology ◽

10.1152/jn.2000.84.5.2225 ◽

2000 ◽

Vol 84 (5) ◽

pp. 2225-2236 ◽

Cited By ~ 49

Author(s):

Robert C. Foehring ◽

Paul G. Mermelstein ◽

Wen-Jie Song ◽

Sasha Ulrich ◽

D. James Surmeier

Keyword(s):

Pyramidal Neurons ◽

Cell Types ◽

Calcium Currents ◽

Medium Spiny Neurons ◽

Cell Type ◽

Channel Current ◽

Spiny Neurons ◽

Deactivation Kinetics ◽

Whole Cell Recordings ◽

Neocortical Pyramidal Neurons

Whole cell recordings from acutely dissociated neocortical pyramidal neurons and striatal medium spiny neurons exhibited a calcium-channel current resistant to known blockers of L-, N-, and P/Q-type Ca2+ channels. These R-type currents were characterized as high-voltage–activated (HVA) by their rapid deactivation kinetics, half-activation and half-inactivation voltages, and sensitivity to depolarized holding potentials. In both cell types, the R-type current activated at potentials relatively negative to other HVA currents in the same cell type and inactivated rapidly compared with the other HVA currents. The main difference between cell types was that R-type currents in neocortical pyramidal neurons inactivated at more negative potentials than R-type currents in medium spiny neurons. Ni2+ sensitivity was not diagnostic for R-type currents in either cell type. Single-cell RT-PCR revealed that both cell types expressed the α1E mRNA, consistent with this subunit being associated with the R-type current.

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P.0733 Ensemble dynamics of the direct and indirect pathways of medium spiny neurons in a freely moving DYT-TOR1A dystonic mouse model

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.10.801 ◽

2021 ◽

Vol 53 ◽

pp. S535-S536

Author(s):

F. França de Barros ◽

M.D. Mendonça ◽

S. Knorr ◽

L. Rauschenberger ◽

C.W. Ip ◽

...

Keyword(s):

Mouse Model ◽

Medium Spiny Neurons ◽

Spiny Neurons ◽

Freely Moving

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Remodeling of the dendritic structure of the striatal medium spiny neurons accompanies behavioral recovery in a mouse model of Parkinson's disease

Neuroscience Letters ◽

10.1016/j.neulet.2013.10.049 ◽

2013 ◽

Vol 557 ◽

pp. 95-100 ◽

Cited By ~ 11

Author(s):

Wonju Kim ◽

Mi Jung Im ◽

Cheol Hyoung Park ◽

C. Justin Lee ◽

Sukwoo Choi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Dendritic Structure ◽

Medium Spiny Neurons ◽

Behavioral Recovery ◽

Spiny Neurons

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Cell-type and endocannabinoid specific synapse connectivity in the adult nucleus accumbens core

10.1101/613497 ◽

2019 ◽

Author(s):

Marion A. Deroche ◽

Olivier Lassalle ◽

Olivier J. Manzoni

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Basolateral Amygdala ◽

Ventral Hippocampus ◽

Cb1 Receptors ◽

Medium Spiny Neurons ◽

Cell Type ◽

Spiny Neurons ◽

Trpv1 Receptors ◽

Specific Manner

ABSTRACTThe nucleus accumbens (NAc) is a mesocorticolimbic structure that integrates cognitive, emotional and motor functions. Although its role in psychiatric disorders is widely acknowledged, the understanding of its circuitry is not complete. Here we combined optogenetic and whole-cell recordings to draw a functional portrait of excitatory disambiguated synapses onto D1 and D2 medium spiny neurons (MSNs) in the adult mouse NAc core. Comparing synaptic properties of ventral hippocampus (vHipp), basolateral amygdala (BLA) and prefrontal cortex (PFC) inputs revealed a hierarchy of synaptic inputs and feedforward inhibition that depends on the identity of the postsynaptic target MSN. Thus, the BLA is the dominant excitatory pathway onto D1 MSNs (BLA > PFC = vHipp) while PFC inputs dominate D2 MSNs (PFC > vHipp > BLA). Feedforward inhibition of MSN firing too, was input and cell-type specific: while minimal at vHipp-D1 and vHipp-D2 inputs; it inhibited with similar efficacy BLA-D1 or BLA-D2 inputs, was minimal at PFC-D1 but maximal at PFC-D2 inputs. We also tested the hypothesis that endocannabinoids endow excitatory circuits with pathway- and cell-specific plasticity. Thus, while CB1 receptors (CB1R) uniformly depress excitatory pathways irrespective of MSNs identity, TRPV1 receptors (TRPV1R) bidirectionally control inputs onto the NAc core in a pathway-specific manner. Finally, we show how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses. Together these data shed new light on synapse and circuit specificity in the adult NAc core and illustrate how endocannabinoids contribute to pathway-specific synaptic plasticity.SIGNIFICANCE STATEMENTWe examined the impact of connections from the ventral hippocampus (vHipp,) basolateral amygdala (BLA) and prefrontal cortex (PFC) onto identified medium spiny neurons (MSN) in the adult accumbens core. We found BLA inputs were strongest at D1 MSNs while PFC inputs dominate D2 MSNs. We evaluated the role of the endocannabinoid system in pathway- and cell-specific plasticity and found that CB1 receptors (CB1R) and TRPV1 receptors (TRPV1R) bidirectionally control synaptic transmission and plasticity onto accumbens’ MSNs in a pathway- and cell-specific manner. Finally, we clarify how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses.

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Transcriptional Diversity of Medium Spiny Neurons in the Primate Striatum

10.1101/2020.10.25.354159 ◽

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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