No abstract

The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington’s disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.

Progressive degeneration of dopaminergic neurons, immune activation, and α-synuclein pathology characterize Parkinson’s disease (PD). We previously reported that unilateral intranigral injection of recombinant adeno-associated viral (rAAV) vectors encoding wild-type human α-synuclein produced a rat model of early PD with dopamine terminal dysfunction. Here we tested the hypothesis that decreases in dopamine result in increased postsynaptic dopamine D2/D3 receptor expression, neuroinflammation, and reduced synaptic vesicle glycoprotein 2A (SV2A) density. Rats were injected with rAAV encoding α-synuclein or green fluorescent protein and subjected to non-pharmacological motor tests, before euthanization at 12 weeks post-injection. We performed: 1) in situ hybridization of nigral tyrosine hydroxylase mRNA, 2) HPLC of striatal dopamine content, and 3) autoradiography with [3H]raclopride, [3H]DTBZ, [3H]GBR12935, [3H]PK11195, and [3H]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mitochondrial translocator protein, and SV2A, respectively. rAAV-α-synuclein induced motor asymmetry and reduced tyrosine hydroxylase mRNA and dopamine content in ipsilateral brain regions. This was paralleled by elevated ipsilateral postsynaptic dopamine D2/3 receptor expression and immune activation, with no changes to synaptic SV2A density. In conclusion, α-synuclein overexpression results in dopaminergic degeneration that induced compensatory increases in D2/3 binding and immune activation, recapitulating many of the pathological characteristics of PD.

No abstract

The current data clearly indicate that low concentrations of DOM given to rats in their second week of life induces long-term changes in α-adrenoceptor binding in rat brain that may have relevance to the progression of an epilepsy phenotype.