PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity

Homozygous or compound hetero- zygous mutations in the phosphatase and tensin homolog-induced putative kinase 1 (PINK1 )g ene are causative of autosomal recessive, early onset Parkin- son's disease. Single heterozygous mutations have been detected repeatedly both in a subset of patients and in unaffected individuals, and the significance of these mutations has long been debated. Several neurophysio- logical studies from non-manifesting PINK1 heterozy- gotes have demonstrated the existence of neural plasticity abnormalities, indicating the presence of spe- cific endophenotypic traits in the heterozygous state. We performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knockout (PINK1 1/2 ) mice using a multidisciplinary approach and observed that, despite normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depres- sion was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, a significantly lower dopamine release was measured in the striatum of PINK1 1/2 mice compared with control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmaco- logical agents capable of increasing the availability of dopamine in the synaptic cleft restored normal LTP in heterozygous mice. Moreover, monoamine oxidase B inhibitors rescued physiological LTP and normal dopa- mine release. Our results provide novel evidence for striatal plasticity abnormalities, even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of Parkinson's disease and a valid tool with which to characterize early disease stage and design possible disease-modifying therapies. V C 2013 International Parkinson and Movement Disorder Society