scholarly journals 3475 A TL1 Team Approach to CNS-Localized Delivery of Neurotrophic Factors for Treatment of Parkinson’s Disease

2019 ◽  
Vol 3 (s1) ◽  
pp. 129-130
Author(s):  
Adithya Gopinath ◽  
Shaheen Farhadi
Keyword(s):  
Dopaminergic Neurons ◽  
Standard Of Care ◽  
Team Approach ◽  
Midbrain Dopaminergic Neurons ◽  
Post Mortem Brain ◽  
Galectin 3 ◽  
Study Population ◽  
Localized Delivery ◽  
Dopamine Signaling ◽  
Tissue Site

OBJECTIVES/SPECIFIC AIMS: We present an alternative strategy to retain NTFs at an injected CNS tissue site by endowing them with binding affinity for carbohydrates that are abundant on the cell surface and within extracellular matrices. METHODS/STUDY POPULATION: We are creating recombinant fusions in which glial cell-derived neurotrophic factor (GDNF) is linked to galectin-3 (G3), a human protein that binds to extracellular beta-galactoside glycans and glycosaminoglycans. GDNF-G3 fusion proteins will circumvent major therapeutic shortcomings of early GDNF human trials by anchoring GDNF to the midbrain in a preclinical animal model of PD over a therapeutically-relevant timescale in order to achieve DA neuron rescue. Further, in PD patients, we have detected significantly dysregulated dopamine signaling in peripheral, blood-derived monocytes, suggesting a systemic dopamine signaling change in PD. RESULTS/ANTICIPATED RESULTS: Based on results from published human NTF administration trials, we anticipate that a successful intervention using GDNF-G3 will result in rescue or delayed degeneration of midbrain dopaminergic neurons in a murine PD model. Outcome measures include behavioral PD phenotype testing via rotarod and pole descent compared to non-parkinsonian control animals, as well as corroborating immunohistological evidence from immunohistochemical examination of post-mortem brain tissue from the same animals to examine degree of degeneration. DISCUSSION/SIGNIFICANCE OF IMPACT: Current treatments for PD, whether pharmacological or surgical, center on alleviating movement symptoms that impair daily function - in other words, largely palliative care. Little has been accomplished by way of rescue of dopaminergic neurons or slowing disease progression using standard-of-care therapy. If successful, GDNF-G3 constructs administered intracranially at the site of degeneration would represent a milestone on the path to treating the basic pathology associated with PD, while addressing major shortcomings in earlier NTF-delivery attempts, namely NTF diffusion away from target site.

scholarly journals ADHD-like behaviors caused by inactivation of a transcription factor controlling the balance of inhibitory and excitatory neuron development in the mouse anterior brainstem

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesca Morello ◽  
Vootele Voikar ◽  
Pihla Parkkinen ◽  
Anne Panhelainen ◽  
Marko Rosenholm ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dopaminergic Neurons ◽  
Dopaminergic System ◽  
Developmental Pathways ◽  
Neuron Development ◽  
Learning Deficits ◽  
Glutamatergic Neurons ◽  
Midbrain Dopaminergic Neurons ◽  
Dopamine Signaling ◽  
Neurochemical Changes

Abstract The neural circuits regulating motivation and movement include midbrain dopaminergic neurons and associated inhibitory GABAergic and excitatory glutamatergic neurons in the anterior brainstem. Differentiation of specific subtypes of GABAergic and glutamatergic neurons in the mouse embryonic brainstem is controlled by a transcription factor Tal1. This study characterizes the behavioral and neurochemical changes caused by the absence of Tal1 function. The Tal1cko mutant mice are hyperactive, impulsive, hypersensitive to reward, have learning deficits and a habituation defect in a novel environment. Only minor changes in their dopaminergic system were detected. Amphetamine induced striatal dopamine release and amphetamine induced place preference were normal in Tal1cko mice. Increased dopamine signaling failed to stimulate the locomotor activity of the Tal1cko mice, but instead alleviated their hyperactivity. Altogether, the Tal1cko mice recapitulate many features of the attention and hyperactivity disorders, suggesting a role for Tal1 regulated developmental pathways and neural structures in the control of motivation and movement.

scholarly journals 4053 A TL1 Team Approach to CNS-Localized Delivery of Glial Cell-Derived Neurotrophic Factor for Treatment of Parkinson’s Disease

2020 ◽  
Vol 4 (s1) ◽  
pp. 1-1
Author(s):  
Shaheen Farhadi ◽  
Adithya Gopinath ◽  
Wolfgang Streit ◽  
Gregory A Hudalla ◽  
Habibeh Khoshbouei
Keyword(s):  
Cell Surface ◽  
Dopaminergic Neurons ◽  
Fusion Proteins ◽  
Ex Vivo ◽  
Symptomatic Relief ◽  
Dopamine Neuron ◽  
Team Approach ◽  
Depth Of Penetration ◽  
Tissue Surfaces ◽  
Galectin 3

OBJECTIVES/GOALS: Develop a strategy to restrict GDNF diffusion at an injected CNS tissue site for dopamine neuron rescue by endowing it with binding affinity for carbohydrates that are abundant on the cell surface and extracellular matrix. METHODS/STUDY POPULATION: GDNF will be fused to galectin-3 (G3), a human protein that binds to β-galactoside residues of cell surface and matrix glycoproteins. We characterized the binding of G3 fusion proteins to various glycoproteins and primary human myeloid cells. We incubated G3 fusions with CNS tissue ex vivo to measure their binding and depth of penetration via diffusion. We next plan to administer GDNF-G3 via CNS intracranial infusion in a murine PD model and then conduct behavioral PD phenotype testing via rotarod and pole descent to compare to non-parkinsonian controls. We will further examine the effects of GDNF-G3 on degeneration using immunohistochemical examination of post-mortem brain tissue. RESULTS/ANTICIPATED RESULTS: Based on results from previous clinical trials of GDNF delivery, we anticipate that a successful intervention using GDNF-G3 will result in rescue of midbrain dopaminergic neurons in a murine PD model. In murine CNS tissue, we observed binding to glycans at the tissue surfaces when incubated with G3 fusion proteins ex vivo, suggesting GDNF-G3 will remain localized to the injection site. Next we will administer GDNF-G3 via CNS intracranial infusion in a murine PD model and assess efficacy by behavior and histopathology. GDNF-G3-mediated dopamine neuron rescue are expected to slow or reverse the progression of PD in these animal models. DISCUSSION/SIGNIFICANCE OF IMPACT: PD treatments focus on symptomatic relief. Standard therapies have not been efficacious in rescuing of dopaminergic neurons. GDNF-G3 administered at the site of neurodegeneration would represent a milestone on the path to treating PD pathology and address limitations of GDNF delivery.

scholarly journals Neurotensin Induces Presynaptic Depression of D2 Dopamine Autoreceptor-Mediated Neurotransmission in Midbrain Dopaminergic Neurons

2015 ◽  
Vol 35 (31) ◽  
pp. 11144-11152 ◽  
Author(s):  
E. Piccart ◽  
N. A. Courtney ◽  
S. Y. Branch ◽  
C. P. Ford ◽  
M. J. Beckstead
Keyword(s):  
Dopaminergic Neurons ◽  
Dopamine Autoreceptor ◽  
Midbrain Dopaminergic Neurons

Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

2021 ◽  
Vol 118 (40) ◽  
pp. e2111069118
Author(s):  
Theodoros Tsetsenis ◽  
Julia K. Badyna ◽  
Julianne A. Wilson ◽  
Xiaowen Zhang ◽  
Elizabeth N. Krizman ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dorsal Hippocampus ◽  
Memory Formation ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Aversive Learning ◽  
Contextual Fear ◽  
Dopaminergic Transmission ◽  
Midbrain Dopaminergic Neurons ◽  
Midbrain Dopamine

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

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