Progressive parkinsonism due to mitochondrial impairment: Lessons from the MitoPark mouse model.

The cardinal pathophysiological finding of Parkinson's disease (PD) is a chronic, progressive degeneration of dopamine (DA) neurons in the substantia nigra, which is responsible for the motor and some of the non-motor symptomatology. While the primary causes of nigrostriatal degeneration are hotly debated, considerable evidence supports a central role for impaired mitochondrial function. Postmortem analysis of PD patients reveals impaired respiratory chains and increased mutations of mitochondrial DNA (mtDNA), in addition to increased markers of oxidative stress indicative of mitochondrial impairment. Most animal models of PD, both genetic and toxin-based, target some component of mitochondrial function to reproduce aspects of the human disease. One model that continues to gain attention is the MitoPark mouse, created through a cell type-specific knockout of mitochondrial transcription factor A specifically in midbrain DA neurons. This model effectively recapitulates the slowly developing, adult onset motor decline seen in PD due to mass loss of DA neurons. MitoPark mice therefore represent an effective tool for studying the sequence of events that occurs in the early stages of DA neuron degeneration following mitochondrial impairment, as well as for testing the efficacy of potential disease-modifying therapies in a progressive model of neurodegeneration. A targeted review of key findings from MitoPark mice has not been published since the early years following the initial report of the model in 2007. The current review synthesizes findings from several groups that are exploring MitoPark mice and discusses implications for the future identification of disease-modifying treatments for PD.

Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters.

Degeneration of substantia nigra pars compacta dopamine neurons is a central feature in the pathology of Parkinson's disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson's disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. Preclinical work has scarcely considered the influence of these 2 factors to disease risk and presentation. Here, we observed a progressive decline in dopamine neuron firing activity in male C57BL/6 mice by 18 months of age, while dopamine neurons from females remained largely unaffected. This was accompanied by increased mRNA expression of PINK1 in both males and females, and PARK2 primarily in males, both of which have been linked to Parkinson's. Since the declining cell properties were accompanied by only slight decreases in locomotion in both sexes, it is likely that these age-related impairments in males represent a vulnerability to further insults that could predispose the neurons to neurodegenerative processes such as in Parkinson's.

Biphasic modulation of parallel fibre synaptic transmission by co-activation of presynaptic GABAA and GABAB receptors in mice.

KEY POINTS: Many excitatory synapses co-express presynaptic GABAA and GABAB receptors, despite their opposing actions on synaptic transmission. It is still unclear how co-activation of these receptors modulates synapse function. We measured presynaptic GABA receptor function at parallel fibre synapses onto stellate cells in the cerebellum using whole-cell patch-clamp recording and photolytic uncaging of RuBi-GABA. Activation of presynaptic GABA receptors results in a transient (∼100 ms) enhancement of synaptic transmission (mediated by GABAA receptors) followed by a long lasting (>500 ms) inhibition of transmission (mediated by GABAB receptors). When activated just prior to high-frequency trains of stimulation, presynaptic GABAA and GABAB receptors work together to reduce short-term facilitation/enhance depression, altering the filtering properties of synaptic transmission. Inhibition of synaptic transmission by GABAB receptors is more sensitive to GABA than enhancement by GABAA receptors, suggesting GABAB receptors may be activated by ambient GABA or release from greater distances. ABSTRACT: GABAA and GABAB receptors are co-expressed at many presynaptic terminals in the central nervous system. Previous studies have shown that GABAA receptors typically enhance vesicle release while GABAB receptors inhibit release. However, it is not clear how the competing actions of these receptors modulate synaptic transmission when co-activated, as is likely in vivo. We investigated this question at parallel fibre synapses in the cerebellum, which co-express presynaptic GABAA and GABAB receptors. In acute slices from C57BL/6 mice, we find that co-activation of presynaptic GABA receptors by photolytic uncaging of RuBi-GABA has a biphasic effect on EPSC amplitudes recorded from stellate cells. Synchronous and asynchronous EPSCs evoked within ∼100 ms of GABA uncaging were increased, while EPSCs evoked ∼300-600 ms after GABA uncaging were reduced compared to interleaved control sweeps. We confirmed these effects are presynaptic by measuring the paired-pulse ratio, variance of EPSC amplitudes, and response probability. During trains of high-frequency stimulation GABAA and GABAB receptors work together (rather than oppose one another) to reduce short-term facilitation when GABA is uncaged just prior to the onset of stimulation. We also find that GABAB receptor-mediated inhibition can be elicited by lower GABA concentrations than GABAA receptor-mediated enhancement of EPSCs, suggesting GABAB receptors may be selectively activated by ambient GABA or release from more distance synapses. These data suggest that GABA, acting through both presynaptic GABAA and GABAB receptors, modulate the amplitude and short-term plasticity of excitatory synapses, a result not possible from activation of either receptor type alone.