scholarly journals Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Polina Kosillo ◽  
Natalie M. Doig ◽  
Kamran M. Ahmed ◽  
Alexander H.C.W. Agopyan-Miu ◽  
Corinna D. Wong ◽  
...  
Keyword(s):  
Cognitive Flexibility ◽  
Behavioral Problems ◽  
Dopamine Release ◽  
Neurodevelopmental Disorder ◽  
Critical Role ◽  
Cell Types ◽  
Dopamine Neurons ◽  
Striatal Dopamine ◽  
Mtorc1 Signaling ◽  
Striatal Dopamine Release

AbstractTuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). TSC is associated with significant cognitive, psychiatric, and behavioral problems, collectively termed TSC-Associated Neuropsychiatric Disorders (TAND), and the cell types responsible for these manifestations are largely unknown. Here we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which modulate cognitive, motivational, and affective behaviors, are involved in TAND. We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release. These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properties of dopamine neurons, and indicate that dopaminergic dysfunction may contribute to cognitive inflexibility in TSC.

scholarly journals Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of DYT1-TOR1A dystonia

2020 ◽  
Author(s):  
Anthony M. Downs ◽  
Xueliang Fan ◽  
Radhika Kadakia ◽  
Yuping Donsante ◽  
H.A. Jinnah ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Ex Vivo ◽  
Dopamine Neurons ◽  
Striatal Dopamine ◽  
Cholinergic Interneurons ◽  
Base Pair Deletion ◽  
Presynaptic Mechanisms ◽  
Conditional Expression ◽  
Striatal Dopamine Release

ABSTRACTDYT1-TOR1A dystonia is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a+/ΔE knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca2+ signaling, D2 dopamine autoreceptor function and GABAB receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons.

VENTRAL STRIATAL DOPAMINE RELEASE AND SENSORIMOTOR GATING

1998 ◽  
Vol 9 (Supplement) ◽  
pp. S95
Author(s):  
L. S. Wilkinson ◽  
T. Humbya ◽  
M. A. Geyer
Keyword(s):  
Dopamine Release ◽  
Sensorimotor Gating ◽  
Striatal Dopamine ◽  
Striatal Dopamine Release

scholarly journals Glycine stimulates striatal dopamine release in conscious rats

1993 ◽  
Vol 110 (1) ◽  
pp. 50-53 ◽  
Author(s):  
Gal Yadid ◽  
Karel Pacak ◽  
Eliahu Golomb ◽  
Judith D. Harvey-White ◽  
Daniel M. Lieberman ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Striatal Dopamine ◽  
Conscious Rats ◽  
Striatal Dopamine Release

scholarly journals Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model

2018 ◽  
Author(s):  
Michal Wegrzynowicz ◽  
Dana Bar-On ◽  
Laura Calo’ ◽  
Oleg Anichtchik ◽  
Mariangela Iovino ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Dopaminergic Neurons ◽  
Dopamine Release ◽  
Striatal Dopamine ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficit ◽  
Promising Therapeutic Approach ◽  
Striatal Dopamine Release

SUMMARYParkinson’s Disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b’s function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.

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