# Optogenetic and Chemogenetic Dissection of Cell Transplants

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2021 · $351,912

## Abstract

Parkinson's disease (PD) causes disability in an estimated 1 million Americans and is characterized by
progressive loss of dopaminergic neurons that originate in the substantia nigra pars compacta (SNpc) and their
axons. Levodopa (LD) in some form is required to control symptoms of PD in vast majority of patients, but its
use causes drug-induced dyskinesias (DID), motor and non motor fluctuations, disabling complications that
remains a major problem in contemporary management of PD. Intermittent high dose LD treatments, loss of
continuous dopaminergic stimulation (CDS) along with dopamine receptor super sensitivity are hypothesized
as causative factors for DID and fluctuations. It is also well accepted that information transfer from the motor
cortex to the basal ganglia and back is abnormal in PD and correction of electrophysiological abnormalities
may be critical to provide symptomatic relief to patients with advanced PD. Our studies show that the
electrophysiological changes that occur in the basal ganglia as result of parkinsonism remain largely
unmitigated with round the clock LD treatments despite excellent amelioration of parkinsonian behavior. In
contrast, dopaminergic cell transplants into the striatum “normalize” basal ganglia neurophysiology and
parkinsonian behavioral abnormalities. We show that synaptic connectivity between the graft and the host is
critical and necessary to mediate these effects. These findings suggest that pre-synaptic factors such as the
presence of nigrostriatal synapses that enables focused release of dopamine, its reuptake and regulation via
pre-synaptic receptors may all be important to minimize the motor complications of PD. Recent studies have
shown that dopaminergic cell transplantation for PD can be successful and without deleterious side effects
providing >2 decades of effective anti-parkinsonian benefits to patients. This has led to the lifting of the
moratorium on clinical cell transplantation for PD. However, optimization of cell transplantation techniques
including the ability to externally control the functioning of the grafts and its newly formed synaptic connections
with the host is critical to ensure safety of future clinical translation of such grafts. Therefore, we seek to
comprehensively evaluate the hypothesis that electrophysiological “normalization” in the basal ganglia –
cortical circuit is necessary to mitigate or eliminate DID and fluctuations in PD. Using a highly reproducible rat
model of PD that exhibit DID and fluctuations, optogenetic and chemogenetic modulation of grafts such that
they can be turned “off” and “on”, awake basal ganglia single cell recordings, LFP recordings, EEG and in vivo
microdialysis combined with HPLC-Ms/Ms we plan to study the biochemical and electrical abnormalities in the
basal ganglia and the cortex associated with DID and fluctuations in PD. Multiple nuclei in the basal ganglia
and its known connections will be probed. Extensive histological studies will als...

## Key facts

- **NIH application ID:** 10160983
- **Project number:** 5R01NS104565-04
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** THYAGARAJAN SUBRAMANIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,912
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160983

## Citation

> US National Institutes of Health, RePORTER application 10160983, Optogenetic and Chemogenetic Dissection of Cell Transplants (5R01NS104565-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10160983. Licensed CC0.

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