Abstract
AimsMitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ‐aminobutyric acid (GABA)‐ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease.MethodsHistochemical, immunohistochemical and immunofluorescent assays were performed on post‐mortem brain tissue from 10 patients and 10 age‐matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring.ResultsWe observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss.ConclusionsWe propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease.
Highlights
Mitochondrial diseases are heterogeneous disorders characterized by a wide-ranging spectrum of clinical symptoms and fluctuating disease progression
We investigated the neuropathology of 10 adult patients with mitochondrial disease to determine whether inhibitory interneurones are vulnerable to mtDNA defects and could feasibly contribute to altered neuronal network circuitry in the brain
The overall density of GABAergic interneurones is reduced in many of these patients, implying reduced inhibitory neurotransmission which could contribute to altered network dynamics in the brains of patients
Summary
Mitochondrial diseases are heterogeneous disorders characterized by a wide-ranging spectrum of clinical symptoms and fluctuating disease progression. Recent electrophysiological studies suggest fast-spiking, γ-aminobutyric acid (GABA)-ergic inhibitory interneurones are vulnerable to disruption of complexes I and IV of the mitochondrial respiratory chain [2,3]. This is not surprising as fast-spiking inhibitory interneurones are thought to consume much more energy than other cell types in the brain, and this increased energy requirement originates from their ability to generate and sustain repetitive, high-frequency action potentials that control complex neuronal network oscillations, known as gamma oscillations. Brain regions of interest (ROIs) were selected on the basis of recognized lobar predilection of pathological involvement in the different genotypes including occipital lobe which is commonly involved in patients harbouring POLG mutations, and temporal cortex in patients with m.3243A>G mutations while the frontal cortices are often described as relatively spared and used as a relative control ROI
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