Effects of aging on substantia nigra dopamine neuron excitability and inhibitory synaptic transmission in mice

Abstract

The degeneration of substantia nigra dopamine neurons is involved in the etiology for Parkinson’s disease, which is characterized by progressive loss of motor and cognitive functions. The biggest risk factors for Parkinson’s disease are age and sex; most cases occur after age 60 and prevalence is almost two times greater in men than women. While much research in Parkinson’s has focused on the molecular mechanisms underlying dopamine neuron degeneration, very little work has considered the influence of sex and normal aging on the functioning of dopamine neurons, which may contribute to disease risk and presentation. In this work, we studied intrinsic firing properties and synaptic transmission to substantia nigra dopamine neurons with in vivo single unit recordings and whole cell patch clamp recordings in brain slices in male and female C57Bl/6 mice at ages 4, 18 and 24 months. Dopamine neurons recorded from male mice ages 18 months and older showed disruptions in firing activity and an increased propensity to depolarization block compared with younger males, while neurons from females remained largely unchanged across ages. Also, preliminary data suggest enhanced GABAergic transmission in dopamine neurons with age in males; likely a compensatory mechanism to balance the increased dopamine neuron excitability in order to maintain normal motor functioning. Understanding how aging affects dopamine neuron functioning, as well as the balance of excitatory and inhibitory input can help determine areas in the nigrostriatal circuity that are vulnerable to impaired functioning, such as in Parkinson’s disease, as well as therapeutic targets.Support or Funding InformationNIA grant ‐ R01 AG052606, Presbyterian Health Foundation, Oklahoma Center for Adult Stem Cell Research (OCASCR)