scholarly journals Mutant huntingtin enhances activation of dendritic Kv4 K+ channels in striatal spiny projection neurons

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Luis Carrillo-Reid ◽  
Michelle Day ◽  
Zhong Xie ◽  
Alexandria E Melendez ◽  
Jyothisri Kondapalli ◽  
...  
Keyword(s):  
Zinc Finger Protein ◽  
Ex Vivo ◽  
Brain Slices ◽  
Projection Neurons ◽  
Receptor Signaling ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Trkb Receptor ◽  
Dendritic Excitability ◽  
Kv4 Channels

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. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD.

scholarly journals Enhanced GABAergic Inhibition of Cholinergic Interneurons in the zQ175+/− Mouse Model of Huntington's Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Sean Austin O. Lim ◽  
D. James Surmeier
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Brain Slices ◽  
Projection Neurons ◽  
Gabaergic Inhibition ◽  
Indirect Pathway ◽  
Cholinergic Interneurons ◽  
Specific Alteration

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that initially manifests itself in the striatum. How intrastriatal circuitry is altered by the disease is poorly understood. To help fill this gap, the circuitry linking spiny projection neurons (SPNs) to cholinergic interneurons (ChIs) was examined using electrophysiological and optogenetic approaches in ex vivo brain slices from wildtype mice and zQ175+/− models of HD. These studies revealed a severalfold enhancement of GABAergic inhibition of ChIs mediated by collaterals of indirect pathway SPNs (iSPNs), but not direct pathway SPNs (dSPNs). This cell-specific alteration in synaptic transmission appeared in parallel with the emergence of motor symptoms in the zQ175+/− model. The adaptation had a presynaptic locus, as it was accompanied by a reduction in paired-pulse ratio but not in the postsynaptic response to GABA. The alterations in striatal GABAergic signaling disrupted spontaneous ChI activity, potentially contributing to the network dysfunction underlying the hyperkinetic phase of HD.

scholarly journals A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

2020 ◽  
Author(s):  
Krishnakanth Kondabolu ◽  
Natalie M. Doig ◽  
Olaoluwa Ayeko ◽  
Bakhtawer Khan ◽  
Alexandra Torres ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Subthalamic Nucleus ◽  
Ex Vivo ◽  
Cell Types ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Primary Input ◽  
Cholinergic Interneurons ◽  
Axonal Connections ◽  
Excitatory Responses

AbstractThe striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

scholarly journals Cell type-specific membrane potential changes in dorsolateral striatum accompanying reward-based sensorimotor learning

Function ◽  
2021 ◽  
Author(s):  
Tanya Sippy ◽  
Corryn Chaimowitz ◽  
Sylvain Crochet ◽  
Carl C H Petersen
Keyword(s):  
Membrane Potential ◽  
Dopamine Receptors ◽  
Cell Types ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Indirect Pathway ◽  
Cell Type Specific ◽  
Striatal Membrane ◽  
Sensory Evoked

Abstract The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.

scholarly journals Regulation of dendritic calcium release in striatal spiny projection neurons

2013 ◽  
Vol 110 (10) ◽  
pp. 2325-2336 ◽  
Author(s):  
Joshua L. Plotkin ◽  
Weixing Shen ◽  
Igor Rafalovich ◽  
Luke E. Sebel ◽  
Michelle Day ◽  
...  
Keyword(s):  
Action Potentials ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Release ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
Laser Scanning Microscopy ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Group I

The induction of corticostriatal long-term depression (LTD) in striatal spiny projection neurons (SPNs) requires coactivation of group I metabotropic glutamate receptors (mGluRs) and L-type Ca2+ channels. This combination leads to the postsynaptic production of endocannabinoids that act presynaptically to reduce glutamate release. Although the necessity of coactivation is agreed upon, why it is necessary in physiologically meaningful settings is not. The studies described here attempt to answer this question by using two-photon laser scanning microscopy and patch-clamp electrophysiology to interrogate the dendritic synapses of SPNs in ex vivo brain slices from transgenic mice. These experiments revealed that postsynaptic action potentials induce robust ryanodine receptor (RYR)-dependent Ca2+-induced-Ca2+ release (CICR) in SPN dendritic spines. Depolarization-induced opening of voltage-gated Ca2+ channels was necessary for CICR. CICR was more robust in indirect pathway SPNs than in direct pathway SPNs, particularly in distal dendrites. Although it did not increase intracellular Ca2+ concentration alone, group I mGluR activation enhanced CICR and slowed Ca2+ clearance, extending the activity-evoked intraspine transient. The mGluR modulation of CICR was sensitive to antagonism of inositol trisphosphate receptors, RYRs, src kinase, and Cav1.3 L-type Ca2+ channels. Uncaging glutamate at individual spines effectively activated mGluRs and facilitated CICR induced by back-propagating action potentials. Disrupting CICR by antagonizing RYRs prevented the induction of corticostriatal LTD with spike-timing protocols. In contrast, mGluRs had no effect on the induction of long-term potentiation. Taken together, these results make clearer how coactivation of mGluRs and L-type Ca2+ channels promotes the induction of activity-dependent LTD in SPNs.

scholarly journals Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington's disease

2021 ◽  
Author(s):  
Joshua Callahan ◽  
David L Wokosin ◽  
Mark D Bevan
Keyword(s):  
Basal Ganglia ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Ex Vivo ◽  
Cell Loss ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Cortical Input ◽  
Psychomotor Symptoms

The psychomotor symptoms of Huntington's disease (HD) are linked to degeneration of the basal ganglia indirect pathway. To determine how this pathway is perturbed prior to cell loss, optogenetic- and reporter-guided electrophysiological interrogation approaches were applied to early symptomatic 6-month-old Q175 HD mice. Although cortical activity was unaffected, indirect pathway striatal projection neurons were hypoactive in vivo, consistent with reduced cortical input strength and dendritic excitability. Downstream parvalbumin-expressing prototypic external globus pallidus (GPe) neurons were hyperactive in vivo and exhibited elevated autonomous firing ex vivo. Optogenetic inhibition of prototypic GPe neurons ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative arkypallidal neurons in vivo. In contrast to STN neurons, autonomous arkypallidal activity was unimpaired ex vivo. Together with previous studies, these findings demonstrate that basal ganglia indirect pathway neurons are highly dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic properties 6-12 months before cell loss.

scholarly journals Asymmetrical choice-related ensemble activity in direct and indirect-pathway striatal neurons drives perceptual decisions

2021 ◽  
Author(s):  
Lele Cui ◽  
Shunhang Tang ◽  
Kai Zhao ◽  
Jingwei Pan ◽  
Zhaoran Zhang ◽  
...  
Keyword(s):  
Decision Making ◽  
Action Selection ◽  
Behavioral Effects ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Two Photon ◽  
Decision Making Behavior ◽  
Ensemble Activity ◽  
Deep Brain

Action selection during decision-making depends on the basal ganglia circuits that comprise the direct and indirect pathways known to oppositely control movement. However, the mechanism for coordinating these opponent pathways during decision-making remains unclear. We address this by employing deep-brain two-photon imaging and optogenetic manipulations of the direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) in the posterior striatum during an auditory decision-making behavior. We show that while dSPNs and iSPNs play opposite causal roles during decision-making, each subtype contains divergent ensembles preferring different choices. The ensembles in dSPNs show stronger contralateral dominance than those in iSPNs manifested by higher-level activation and synchronization. Consistent with this asymmetrical contralateral dominance, optogenetic disinhibition of both pathways promoted contralateral choices. A computational model incorporating the striatal ensemble asymmetry recapitulated the causal behavioral effects. Our results uncover the asymmetry between opponent SPN ensembles as a circuit mechanism for action selection during decision-making.

scholarly journals Striatal Control of Movement: A Role for New Neuronal (Sub-) Populations?

2021 ◽  
Vol 15 ◽  
Author(s):  
Tim Fieblinger
Keyword(s):  
Brain Area ◽  
Projection Neurons ◽  
Anatomical Location ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Transcriptional Profiles ◽  
Transcriptional Signature ◽  
Neuronal Populations ◽  
Abnormal Movements ◽  
Two Populations

The striatum is a very heterogenous brain area, composed of different domains and compartments, albeit lacking visible anatomical demarcations. Two populations of striatal spiny projection neurons (SPNs) build the so-called direct and indirect pathway of the basal ganglia, whose coordinated activity is essential to control locomotion. Dysfunction of striatal SPNs is part of many movement disorders, such as Parkinson’s disease (PD) and L-DOPA-induced dyskinesia. In this mini review article, I will highlight recent studies utilizing single-cell RNA sequencing to investigate the transcriptional profiles of striatal neurons. These studies discover that SPNs carry a transcriptional signature, indicating both their anatomical location and compartmental identity. Furthermore, the transcriptional profiles reveal the existence of additional distinct neuronal populations and previously unknown SPN sub-populations. In a parallel development, studies in rodent models of PD and L-DOPA-induced dyskinesia (LID) report that direct pathway SPNs do not react uniformly to L-DOPA therapy, and that only a subset of these neurons is underlying the development of abnormal movements. Together, these studies demonstrate a new level of cellular complexity for striatal (dys-) function and locomotor control.

scholarly journals Cell-type and subcellular compartment-specific APEX2 proximity labeling reveals activity-dependent nuclear proteome dynamics in the striatum

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
V. Dumrongprechachan ◽  
R. B. Salisbury ◽  
G. Soto ◽  
M. Kumar ◽  
M. L. MacDonald ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Functional Organization ◽  
Projection Neurons ◽  
Specific Information ◽  
Striatal Neurons ◽  
Cell Type ◽  
Indirect Pathway ◽  
Subcellular Compartment ◽  
Cell Type Specific ◽  
And Function

AbstractThe vertebrate brain consists of diverse neuronal types, classified by distinct anatomy and function, along with divergent transcriptomes and proteomes. Defining the cell-type specific neuroproteomes is important for understanding the development and functional organization of neural circuits. This task remains challenging in complex tissue, due to suboptimal protein isolation techniques that often result in loss of cell-type specific information and incomplete capture of subcellular compartments. Here, we develop a genetically targeted proximity labeling approach to identify cell-type specific subcellular proteomes in the mouse brain, confirmed by imaging, electron microscopy, and mass spectrometry. We virally express subcellular-localized APEX2 to map the proteome of direct and indirect pathway spiny projection neurons in the striatum. The workflow provides sufficient depth to uncover changes in the proteome of striatal neurons following chemogenetic activation of Gαq-coupled signaling cascades. This method enables flexible, cell-type specific quantitative profiling of subcellular proteome snapshots in the mouse brain.

scholarly journals Distinct neural progenitor pools in the ventral telencephalon generate diversity in striatal spiny projection neurons

2019 ◽  
Author(s):  
Fran van Heusden ◽  
Anežka Macey-Dare ◽  
Rohan N. Krajeski ◽  
Andrew Sharott ◽  
Tommas Jan Ellender
Keyword(s):  
Neural Progenitor ◽  
Neural Progenitors ◽  
Projection Neurons ◽  
Spine Density ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Pulse Label ◽  
Cortical Input ◽  
Intermediate Progenitors ◽  
Lateral Ganglionic Eminence

AbstractHeterogeneous populations of neural progenitors in the embryonic lateral ganglionic eminence (LGE) generate all GABAergic spiny projection neurons (SPNs) found in the striatum. Here we investigate how this diversity in neural progenitors relates to diversity of adult striatal neurons and circuits. Using a combination of in utero electroporation to fluorescently pulse-label striatal neural progenitors in the LGE, brain slice electrophysiology, electrical and optogenetic circuit mapping and immunohistochemistry, we characterise a population of neural progenitors enriched for apical intermediate progenitors (aIPs) and a distinct population of other progenitors (OPs) and their neural offspring. We find that neural progenitor origin has subtle but significant effects on the properties of striatal SPNs. Although aIP and OP progenitors can both generate D1-expressing direct pathway as well as D2-expressing indirect pathway SPNs found intermingled in the striatum, the aIP derived SPNs are found in more medial aspects of the striatum, exhibit more complex dendritic arbors with higher spine density and differentially sample cortical input. Moreover, optogenetic circuit mapping of the aIP derived neurons show that they further integrate within striatal circuits and innervate both local D1 and D2 SPNs. These results show that it is possible to fluorescently pulse-label distinct neural progenitor pools within the LGE and provide the first evidence that neural progenitor heterogeneity can contribute to the diversity of striatal SPNs.

scholarly journals Amygdala-cortical control of striatal plasticity drives the acquisition of goal-directed action

2020 ◽  
Author(s):  
Simon D. Fisher ◽  
Lachlan A. Ferguson ◽  
Jesus Bertran-Gonzalez ◽  
Bernard W. Balleine
Keyword(s):  
Basolateral Amygdala ◽  
Ex Vivo ◽  
Projection Neurons ◽  
Cortical Control ◽  
Indirect Pathway ◽  
Optogenetic Stimulation ◽  
Directed Action ◽  
Directed Learning ◽  
Corticostriatal Plasticity ◽  
Stimulation Of

SummaryThe acquisition of goal-directed action requires the encoding of specific action-outcome associations involving plasticity in the posterior dorsomedial striatum (pDMS). We first investigated the relative involvement of the major inputs to the pDMS argued to be involved in this learning-related plasticity, from prelimbic prefrontal cortex (PL) and from the basolateral amygdala (BLA). Using ex vivo optogenetic stimulation of PL or BLA terminals in pDMS, we found that goal-directed learning potentiated the PL input to direct pathway spiny projection neurons (dSPNs) bilaterally but not to indirect pathway neurons (iSPNs). In contrast, learning-related plasticity was not observed in the direct BLA-pDMS pathway. Using toxicogenetics, we ablated BLA projections to either pDMS or PL and found that only the latter was necessary for goal-directed learning. Importantly, transient inactivation of the BLA during goal-directed learning prevented the PL-pDMS potentiation of dSPNs, establishing that the BLA input to the PL is necessary for the corticostriatal plasticity underlying goal-directed learning.

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