scholarly journals Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

2020 ◽  
Author(s):  
Harry S. Xenias ◽  
Chuyu Chen ◽  
Shuo Kang ◽  
Suraj Cherian ◽  
Xiaolei Situ ◽  
...  
Keyword(s):  
Motor Learning ◽  
Kinase Inhibitor ◽  
Treatment Strategies ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Behavioral Alterations ◽  
Striatal Projection Neurons ◽  
Lrrk2 Kinase ◽  
The Impact ◽  
Striatal Function

AbstractLRRK2 mutations are associated with both familial and sporadic forms of Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 plays critical roles in regulating striatal function. Here, by using knock-in mouse lines that express the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how pathogenic LRRK2 mutations altered striatal physiology. We found that R1441C mice displayed a reduced nigrostriatal dopamine release and hypoexcitability in indirect-pathway striatal projection neurons. These alterations were associated with an impaired striatal-dependent motor learning. This deficit in motor learning was rescued following the subchronic administration of the LRRK2 kinase inhibitor Mli-2. In contrast, though a decreased release of dopamine was observed in the G2019S knock-in mice no concomitant cellular and behavioral alterations were found. In summary, our data argue that the impact of LRRK2 mutations cannot be simply generalized. Our findings offer mechanistic insights for devising treatment strategies for PD patients.

Differential cortical activation of the striatal direct and indirect pathway cells: reconciling the anatomical and optogenetic results by using a computational method

2014 ◽  
Vol 112 (1) ◽  
pp. 120-146 ◽  
Author(s):  
Kenji Morita
Keyword(s):  
D2 Receptor ◽  
Computational Method ◽  
Cortical Activation ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Short Term ◽  
Apparent Contradiction ◽  
Striatal Projection Neurons ◽  
Cortical Inputs ◽  
Stimulation Of

The corticostriatal system is considered to be crucially involved in learning and action selection. Anatomical studies have shown that two types of corticostriatal neurons, intratelencephalic (IT) and pyramidal tract (PT) cells, preferentially project to dopamine D1 or D2 receptor-expressing striatal projection neurons, respectively. In contrast, an optogenetic study has shown that stimulation of IT axons evokes comparable responses in D1 and D2 cells and that stimulation of PT axons evokes larger responses in D1 cells. Since the optogenetic study applied brief stimulation only, however, the overall impacts of repetitive inputs remain unclear. Moreover, the apparent contradiction between the anatomical and optogenetic results remains to be resolved. I addressed these issues by using a computational approach. Specifically, I constructed a model of striatal response to cortical inputs, with parameters regarding short-term synaptic plasticity and anatomical connection strength for each connection type. Under the constraint of the optogenetic results, I then explored the parameters that best explain the previously reported paired-pulse ratio of response in D1 and D2 cells to cortical and intrastriatal stimulations, which presumably recruit different compositions of IT and PT fibers. The results indicate that 1) IT→D1 and PT→D2 connections are anatomically stronger than IT→D2 and PT→D1 connections, respectively, consistent with the previous findings, and that 2) IT→D1 and PT→D2 synapses entail short-term facilitation, whereas IT→D2 and PT→D1 synapses would basically show depression, and thereby 3) repetitive IT or PT inputs have larger overall impacts on D1 or D2 cells, respectively, supporting a recently proposed hypothesis on the roles of corticostriatal circuits in reinforcement learning.

scholarly journals A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations

2017 ◽  
Vol 37 (41) ◽  
pp. 9977-9998 ◽  
Author(s):  
Andrew Sharott ◽  
Federica Vinciati ◽  
Kouichi C. Nakamura ◽  
Peter J. Magill
Keyword(s):  
Projection Neurons ◽  
Indirect Pathway ◽  
Beta Oscillations ◽  
Striatal Projection Neurons

scholarly journals Differential Synaptic Input to External Globus Pallidus Neuronal Subpopulations In Vivo

2020 ◽  
Author(s):  
Maya Ketzef ◽  
Gilad Silberberg
Keyword(s):  
Globus Pallidus ◽  
Synaptic Input ◽  
Membrane Properties ◽  
Projection Neurons ◽  
Inhibitory Input ◽  
Indirect Pathway ◽  
Functional Roles ◽  
Striatal Projection Neurons ◽  
Afferent Inputs

SummaryThe rodent external Globus Pallidus (GPe) contains two main neuronal subpopulations, prototypic and arkypallidal cells, which differ in their cellular properties. Their functional synaptic connectivity is, however, largely unknown. Here, we studied the membrane properties and synaptic inputs to these subpopulations in the mouse GPe. We obtained in vivo whole-cell recordings from identified GPe neurons and used optogenetic stimulation to dissect their afferent inputs from the striatum and subthalamic nucleus (STN). All GPe neurons received barrages of excitatory and inhibitory input during slow wave activity. The modulation of their activity was cell-type specific and shaped by their respective membrane properties and afferent inputs. Both GPe subpopulations received synaptic input from STN and striatal projection neurons (MSNs). STN and indirect pathway MSNs strongly targeted prototypic cells while direct pathway MSNs selectively inhibited arkypallidal cells. We show that GPe subtypes are differently embedded in the basal ganglia network, supporting distinct functional roles.

scholarly journals Parallel Movement-suppressing Striatal Output Pathways

2020 ◽  
Author(s):  
Qiaoling Cui ◽  
Xixun Du ◽  
Isaac Y. M. Chang ◽  
Arin Pamukcu ◽  
Varoth Lilascharoen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Body Movement ◽  
Disease Model ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Direct Pathway ◽  
Striatal Projection Neurons ◽  
6 Hydroxydopamine

AbstractThe classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and how they are involved in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting role of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opponent output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes plastic changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

scholarly journals Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

2019 ◽  
Author(s):  
Katelyn N. Benthall ◽  
Katherine R. Cording ◽  
Alexander H.C.W. Agopyan-Miu ◽  
Emily Y. Chen ◽  
Helen S. Bateup
Keyword(s):  
Motor Learning ◽  
Motor Behavior ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Repetitive Behaviors ◽  
Cortical Activation ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Direct Pathway

AbstractTuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which patients frequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause changes to motor behavior in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and determined the consequences on synaptic function and motor learning. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. In addition, dSPN Tsc1 KO mice have impaired endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum, dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced cortical activation of the striatal direct pathway is a potential contributor to altered motor behaviors in TSC.

scholarly journals Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates

2015 ◽  
Vol 113 (5) ◽  
pp. 1533-1544 ◽  
Author(s):  
Arun Singh ◽  
Li Liang ◽  
Yoshiki Kaneoke ◽  
Xuebing Cao ◽  
Stella M. Papa
Keyword(s):  
Basal Ganglia ◽  
Firing Pattern ◽  
Activity Patterns ◽  
Receptor Activation ◽  
Firing Frequency ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Response Compatible ◽  
Motor Abnormalities ◽  
The Impact

Nigrostriatal dopamine denervation plays a major role in basal ganglia circuitry disarray and motor abnormalities of Parkinson's disease (PD). Studies in rodent and primate models have revealed that striatal projection neurons, namely, medium spiny neurons (MSNs), increase the firing frequency. However, their activity pattern changes and the effects of dopaminergic stimulation in such conditions are unknown. Using single-cell recordings in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates with advanced parkinsonism, we studied MSN activity patterns in the transition to different motor states following levodopa administration. In the “off” state (baseline parkinsonian disability), a burst-firing pattern accompanied by prolonged silences (pauses) was found in 34% of MSNs, and 80% of these exhibited a levodopa response compatible with dopamine D1 receptor activation (direct pathway MSNs). This pattern was highly responsive to levodopa given that bursting/pausing almost disappeared in the “on” state (reversal of parkinsonism after levodopa injection), although this led to higher firing rates. Nonbursty MSNs fired irregularly with marked pausing that increased in the on state in the MSN subset with a levodopa response compatible with dopamine D2 receptor activation (indirect pathway MSNs), although the pause increase was not sustained in some units during the appearance of dyskinesias. Data indicate that the MSN firing pattern in the advanced parkinsonian monkey is altered by bursting and pausing changes and that dopamine differentially and inefficiently regulates these behaviorally correlated patterns in MSN subpopulations. These findings may contribute to understand the impact of striatal dysfunction in the basal ganglia network and its role in motor symptoms of PD.

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