The Movement Disorder Society

MDS 18th International Congress of Parkinson's Disease and Movement Disorders, Volume 29,
June 2014 Abstract Supplement

Movement Disorders 2014
Stockholm, Sweden June 8-12, 2014.


A DREADD approach for acute stimulation of cholinergic neurons of the pedunculopontine nucleus reverses Parkinsonism in the lactacystin model of Parkinson's disease

Pienaar,  I.S., Sharma,  P., Elson,  J.L., de Paula,  V., Dexter,  D.T.

London, United Kingdom

Objective:

We elucidate on anti-parkinsonian benefits associated with DBS of the pedunculopontine nucleus (PPN) by targeting remaining PPN cholinergic neurons in a clinically-relevant rat model of PD.

Background:

PPN cholinergics appear disproportionately vulnerable to Parkinson's disease (PD)-associated pathologies compared to other PPN neuronal subtypes (Pienaar et al, 2013a. Am J Pathol); hence representing a DBS target for alleviating PD symptoms.

Methods:

Genetically restricted recombinase-driver rats, for selective expression of Cre recombinase in cholinergic neurons were rendered parkinsonian via a unihemispheric injection of the proteasome-inhibitor, Lactacystin, into the SNpc (Pienaar et al, 2013b. Brain Struct Funct). Such rats were stereotaxically injected with a Cre-recombinase-dependent viral vector based flip-excision (FLEX) switch system to express engineered Designer Receptors Exclusively Activated by Designer Drugs (DREADD) receptors in PPN cholinergic neurons. Such technology involves mutation of a muscarinic G-protein coupled receptor (GPCR), by which the ability to bind to natural ligands is lost, but nanomolar potency is gained for the otherwise pharmacologically inert ligand, clozapine-N-oxide (CNO). This approach allowed us to specifically and inducibly increase activity of remaining PPN cholinergic neurons chemical-genetically in this rat model of PD for investigating the effects in freely moving rats.

Results:

C-fos expression analysis within PPN cholinergic neurons co-expressing fluorescently-tagged DREADD confirmed that CNO selectively activates PPN cholinergic activity in vivo. In vivo electrophysiological monitoring confirmed increased firing of PPN cholinergic neurons. Moreover, behavior tests detected a dramatic reversal of motor symptoms relating to PPN function, following CNO administration to parkinsonian rats compared to sham-lesioned control ones, with both groups injected intra-PPN with the DREADD construct. Increased stereotypic behavior was seen at this CNO dose (1 mg/kg) in both groups.

Conclusions:

We prove that DREADD technology applied to a transgenic Cre-recombinase rat system offers a minimally-invasive means for controlling mammalian brain function and that select activation of cholinergic PPN neurons in parkinsonian brains can remedy motor symptoms.

To cite this abstract, please use the following information:
Pienaar, I.S., Sharma, P., Elson, J.L., de Paula, V., Dexter, D.T.; A DREADD approach for acute stimulation of cholinergic neurons of the pedunculopontine nucleus reverses Parkinsonism in the lactacystin model of Parkinson's disease [abstract]. Movement Disorders 2014;29 Suppl 1 :381