Attention-deficit/hyperactivity disorder-related psychomotor activity and altered neuronal activity in the medial prefrontal cortex and striatum in the A53T mouse model of Parkinson's disease and other synucleinopathies: Findings from an “endophenotype” approach

Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with an increased risk of Parkinson's disease (PD) and other synucleinopathies later in life. The severity of the ADHD phenotype may play a significant role in this association. There is no indication that any of the existing animal models can unify these disorders. Using the Open Field Test, amphetamine-challenge test, Western blot and immunohistochemical analysis of neuronal activity markers (c-Fos, FosB and ΔFosB) we performed a deliberate neurobehavioral characterization of 6-month-old hemizygous A53T carriers (A53T+) of the JAX006823 strain, evaluating the utility of this transgenic mouse model of PD and other synucleinopathies in ADHD/PD continuum research. Adhering to the "endophenotype" approach, non-transgenic littermates (A53T-) and C57BL/6J mice (used to maintain the colony) were examined with A53T+ mice, to differentiate between biomarkers of transgenicity and endophenotypic traits related to the genetic background of the strain. Obtained results revealed that increased behavioral and acute striatal response to novelty, increased basal neuronal activity of the ventromedial prefrontal cortex and rate-dependent calming effect of amphetamine were endophenotypic characteristics of the strain. Increased acute response of the medial prefrontal cortex to novelty and chronic increase in neuronal activity of the striatum appeared as the mark of transgenicity. To the best of our knowledge, this is the first study to indicate external validity of a transgenic mouse model of PD and other synucleinopathies with the neurobehavioral pathology associated with ADHD, hinting at its potential in preclinical research of ADHD/PD continuum. The full capacity of the model remains to be explored.