Aims Mitochondrial 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. Methods Histochemical, 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 GABA ergic 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. Results We observed significant, global reductions in complex I expression within GABA ergic 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.8344 A > G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABA ergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. Conclusions We 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.

Interventions to treat cerebral palsy should be initiated as soon as possible in order to restore the nervous system to the correct developmental trajectory. One drawback to this approach is that interventions have to undergo exceptionally rigorous assessment for both safety and efficacy prior to use in infants. Part of this process should involve research using animals but how good are our animal models? Part of the problem is that cerebral palsy is an umbrella term that covers a number of conditions. There are also many causal pathways to cerebral palsy, such as periventricular white matter injury in premature babies, perinatal infarcts of the middle cerebral artery, or generalized anoxia at the time of birth, indeed multiple causes, including intra-uterine infection or a genetic predisposition to infarction, may need to interact to produce a clinically significant injury. In this review, we consider which animal models best reproduce certain aspects of the condition, and the extent to which the multifactorial nature of cerebral palsy has been modeled. The degree to which the corticospinal system of various animal models human corticospinal system function and development is also explored. Where attempts have already been made to test early intervention in animal models, the outcomes are evaluated in light of the suitability of the model.

Many patients with mitochondrial disease have neurological symptoms, including drug-refractory epilepsy. Chan et al. develop an in vitro model of mitochondrial epilepsy with face and predictive validity. The model provides mechanistic insights into the role of astrocytes and the GABA-glutamate-glutamine cycle in driving seizure generation.

Extensive study has demonstrated that epilepsy occurs with greater frequency at certain times in the 24‐h cycle. Although these findings implicate an overlap between the circadian rhythm and epilepsy, the molecular and cellular mechanisms underlying this circadian regulation are poorly understood. Because the 24‐h rhythm is generated by the circadian molecular system, it is not surprising that this system comprised of many circadian genes is implicated in epilepsy. We summarized evidence in the literature implicating various circadian genes such as Clock, Bmal1, Per1, Rev‐erb⍺, and Ror⍺ in epilepsy. In various animal models of epilepsy, the circadian oscillation and the steady‐state level of these genes are disrupted. The downstream pathway of these genes involves a large number of metabolic pathways associated with epilepsy. These pathways include pyridoxal metabolism, the mammalian target of rapamycin pathway, and the regulation of redox state. We propose that disruption of these metabolic pathways could mediate the circadian regulation of epilepsy. A greater understanding of the cellular and molecular mechanism of circadian regulation of epilepsy would enable us to precisely target the circadian disruption in epilepsy for a novel therapeutic approach.