Homozygous or compound heterozygous mutations in the phosphatase and tensin 
homolog-induced putative kinase 1 (PINK1) gene are causative of autosomal 
recessive, early onset Parkinson'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 neurophysiological studies from non-manifesting PINK1 heterozygotes have 
demonstrated the existence of neural plasticity abnormalities, indicating the 
presence of specific endophenotypic traits in the heterozygous state. We 
performed a functional analysis of corticostriatal synaptic plasticity in 
heterozygous PINK1 knockout (PINK1(+/-) ) 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 depression 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(+/-) mice compared with control 
mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a 
major determinant for the LTP deficit. Accordingly, pharmacological 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 dopamine 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.