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• W2948588876 abstract "Neuronal networks maintain stable activity around a given set point, an enigmatic variable in homeostatic systems. In this issue of Neuron, Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar now show that set points are regulated by mitochondria and propose a potential strategy to treat refractory forms of epilepsy. Neuronal networks maintain stable activity around a given set point, an enigmatic variable in homeostatic systems. In this issue of Neuron, Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar now show that set points are regulated by mitochondria and propose a potential strategy to treat refractory forms of epilepsy. Neurons in the central nervous system are extensively interconnected to form networks. These neuronal networks have to master complex tasks: they need to be stable to store memories but also have to be plastic to allow for learning and the formation of new memories. Past research suggests that stable neuronal activity is accomplished by a homeostatic control system that regulates the properties of neuronal networks, e.g., the mean firing rate (Davis, 2013Davis G.W. Homeostatic signaling and the stabilization of neural function.Neuron. 2013; 80: 718-728Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). Deviations of network properties from the norm, the set point, are monitored by sensors. Homeostatic compensatory mechanisms return the network to its original state (Figure 1). Failure of such control mechanisms will ultimately result in circuit instability, and this characterizes neurological diseases, including epilepsy (Swann and Rho, 2014Swann J.W. Rho J.M. How is homeostatic plasticity important in epilepsy?.Adv. Exp. Med. Biol. 2014; 813: 123-131Crossref PubMed Google Scholar). Thus, understanding how set points are established and adapted to a new state is critical to understand and treat such neurological diseases. While several processes implicated in homeostatic compensation have been identified (Davis, 2013Davis G.W. Homeostatic signaling and the stabilization of neural function.Neuron. 2013; 80: 718-728Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar), one of the key components, the set point, has remained enigmatic. How is the set point established in a neuronal network? Is the set point an adjustable variable? If so, is the set-point regulation distinct from homeostatic feedback responses? In this issue of Neuron, Slutsky and colleagues (Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar) hypothesized that metabolic signaling is a crucial regulator of neuronal homeostasis and thereby elucidate a novel and unexpected regulatory mechanism of the set point (Figure 1). Consequently, their findings open new avenues toward treating neuronal hyperexcitability in epilepsy patients. Given the high-energy demand of neuronal activity in the brain, metabolic alterations affect neuronal activity patterns (Shetty et al., 2012Shetty P.K. Galeffi F. Turner D.A. Cellular links between neuronal activity and energy homeostasis.Front. Pharmacol. 2012; 3: 43Crossref PubMed Scopus (51) Google Scholar). Indeed, accumulating evidence suggests a correlation between impaired metabolic and epileptic neuronal states (Lutas and Yellen, 2013Lutas A. Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy.Trends Neurosci. 2013; 36: 32-40Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). To identify metabolic regulators in epilepsy, Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar utilized transcriptome datasets and genome-scale modeling of epilepsy patients and rat epilepsy models to determine a common metabolic state of epilepsy. An additional “in silico knockout screen” made predictions of which genes would be able to convert the epileptic metabolic state to a healthy, epilepsy-resistant state. Interestingly, the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) emerged as one of the most promising and common candidates. Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar observed a robust and strikingly stable decrease of mean firing rate in a high-density hippocampal culture grown on a multi-electrode array after pharmacological inhibition of DHODH using teriflunomide (TERI). Genetic inhibition of the enzyme DHODH showed identical results, indicating specificity. This pronounced drop in firing rate with TERI was reversible and, when TERI was removed, high-frequency firing in the neuronal network recovered. Surprisingly and in contrast to other activity-dependent perturbations, the reduced mean firing rate in the continuous presence of TERI was not compensated and did not recover during the 2 days of continuous recording. This suggests that TERI blocked the homeostatic regulation following DHODH inhibition. To elucidate how DHODH inactivation reduces the spontaneous firing rates, Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar investigated DHODH’s known functions. DHODH resides at the inner mitochondrial membrane and is implicated in de novo pyrimidine biosynthesis and in the mitochondrial electron transport chain. Biochemical analysis and modulation of uridine levels allowed Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar to exclude a pyrimidine-dependent mechanism. Instead, their work indicated that DHODH inhibition resulted in a partial mitochondrial inhibition that stably decreased spare respiratory capacity while leaving presynaptic ATP levels or the number of mitochondria unaffected. As the spare respiratory capacity is linked to cytosolic and mitochondrial Ca2+ levels, Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar examined presynaptic Ca2+ buffering upon DHODH inhibition with advanced fluorescent imaging. Interestingly, TERI application reduced resting mitochondrial Ca2+ levels but facilitated activity-dependent mitochondrial Ca2+ buffering. Consequently, the altered mitochondrial Ca2+ buffering led to increased resting cytoplasmic Ca2+ levels and decreased Ca2+ transients during neuronal activity. These results are in agreement with the proposed role of mitochondria to modulate cytoplasmic Ca2+ levels (Kwon et al., 2016Kwon S.-K. Sando 3rd, R. Lewis T.L. Hirabayashi Y. Maximov A. Polleux F. LKB1 regulates mitochondria-dependent presynaptic calcium clearance and neurotransmitter release properties at excitatory synapses along cortical axons.PLoS Biol. 2016; 14: e1002516Crossref PubMed Scopus (80) Google Scholar) but at the same time leave interesting open questions: how does DHODH alter the Ca2+ buffering levels, and are other Ca2+ sensors involved as well? When a perturbation is chronically applied to a neuronal network, homeostatic regulation will typically result in the recovery of network activity, i.e., the activity returns to the original set point. One such mechanism is to modulate the intrinsic excitability of neurons by changing the ion channel composition on the neuronal surface. Another mechanism is to tune neurotransmitter release by changing miniature excitatory postsynaptic current (mEPSC) amplitude and frequency (Davis, 2013Davis G.W. Homeostatic signaling and the stabilization of neural function.Neuron. 2013; 80: 718-728Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). However, Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar failed to observe any adaptations of intrinsic excitability, mEPSC amplitude, or frequency. Thus, DHODH inhibition failed to induce a classic homeostatic compensatory response. Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar suggest that DHODH inhibition may have imposed a new set point but that it did not abolish homeostatic regulation at this new set point. To test this idea, they investigated whether activity-dependent compensatory feedback mechanisms are still active under DHODH inhibition. Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar added the GABAB receptor agonist baclofen to hippocampal networks that were treated with TERI. Baclofen acutely reduced mean firing rate, but despite the presence of TERI, the decreased mean firing rate gradually restored to the TERI-dependent new set point. However, this renormalization following baclofen was impaired in conditions of partial mitochondrial uncoupling (1μM Bam15), indicating that set-point adaptation by DHODH inhibition does not impair mitochondrial homeostatic feedback responses. If DHODH is indeed a regulator of activity set points, the renormalization to a new set point should occur in conditions of both increased and decreased firing rates. Therefore, Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar applied TBOA, a glutamate transporter antagonist. This acutely increased mean firing rate, and under normal conditions, the firing rate returned to the set point. Co-application of TERI alters the set point, but it does not block the homeostatic regulation that occurs. These data show that the homeostatic systems are still active under DHODH inhibition. The next steps will now be to identify the molecular pathways in set-point regulation by mitochondrial DHODH and to identify the master regulators for homeostatic responses in neuronal networks. Pathway perturbations that do not elicit homeostatic compensation to the TERI-induced set point are good candidates. One possibility are protein homeostasis pathways as they have been shown to affect synaptic plasticity and neuronal health (Uytterhoeven et al., 2015Uytterhoeven V. Lauwers E. Maes I. Miskiewicz K. Melo M.N. Swerts J. Kuenen S. Wittocx R. Corthout N. Marrink S.J. et al.Hsc70-4 deforms membranes to promote synaptic protein turnover by endosomal microautophagy.Neuron. 2015; 88: 735-748Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Too much or too little protein turnover at synapses perturbs neurotransmission and leads to neurodegeneration. It will be interesting to explore this route and determine a role for protein turnover pathways as regulators of homeostatic response. Energy metabolism requirements can differ in vivo and in vitro. Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar recognized this and tested whether DHODH inhibition modulates spiking activity in vivo. They applied TERI in mouse brain via intracerebroventricular (i.c.v.) infusion and performed in vivo electrophysiological recordings in behaving mice. TERI injections reduced spontaneous spiking activity by 60% in CA1 neurons compared to control mice. In addition, evoked responses in anesthetized mice showed reduced input-output (IO) curves and improved short-term plasticity upon TERI injection in the CA3-CA1 circuit. This is strikingly similar to the effect they saw in acute hippocampal slices in vitro. Providing explanations for how homeostatic plasticity is maintained in conditions with diminished respiratory capacity during DHODH inhibition, Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar propose that lowering the set point reduces the need for respiratory capacity. This results in maintaining metabolic homeostasis and neuronal health in hippocampal circuits. Thus, lowering the set point may be an adaptive strategy to cope with the diminished respiratory capacity without sacrificing the possibility of homeostatic plasticity. Epilepsy may be the result of faulty set points. If this is true, DHODH inhibition may be relevant for counteracting epilepsy. The Slutsky group therefore injected TERI i.c.v. in a pentylenetetrazole (PTZ)-induced epilepsy mouse model. i.c.v. pre-treatment with TERI for 3 days significantly reduced the number of and susceptibility to epileptic seizures. In addition, TERI application to PTZ-treated cultured hippocampal neurons further corroborated the inhibitory long-term effects of TERI on spontaneous and evoked neuronal activity (and Ca2+ levels in cytoplasm and mitochondria). Similarly, the genetic mouse model of Dravet syndrome, which is resistant to the current anti-epileptic medications, showed reduced electrophysiological features of epilepsy and reduced susceptibility to seizures when injected with TERI. These results suggest that DHODH inhibition by TERI may be a promising therapeutic strategy for refractory epilepsy. The computational approach taken by Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar is refreshing and valuable in identifying important regulators of neuronal circuitry level output, and it will be interesting to use similar technology to identify additional components. The identification of a target (and a compound) that can lower the set point of excitatory synaptic transmission in a fashion independent from homeostatic compensatory mechanisms is exciting and of relevance to disease. In epilepsy, excitatory set points appear to be incorrectly positioned, and lowering the set point in epilepsy disease models, including a model that is refractory to the current anti-epileptic drugs, appears beneficial. TERI treatment seems to suppress hyperexcitability by preventing mitochondrial Ca2+ overload, and this is different from the known metabolic anti-epileptic strategies like ketogenic diet and stiripentol. TERI treatment was effective in a mouse model of Dravet syndrome, and it would be interesting to determine the effectiveness in other refractory epilepsy syndromes, like DOORS syndrome (Campeau et al., 2014Campeau P.M. Kasperaviciute D. Lu J.T. Burrage L.C. Kim C. Hori M. Powell B.R. Stewart F. Félix T.M. van den Ende J. et al.The genetic basis of DOORS syndrome: an exome-sequencing study.Lancet Neurol. 2014; 13: 44-58Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). Interestingly, Alzheimer’s (AD) and Parkinson’s (PD) patients show a higher risk for seizures and epilepsy (Miranda and Brucki, 2014Miranda D.D.C. Brucki S.M.D. Epilepsy in patients with Alzheimer’s disease: a systematic review.Dement. Neuropsychol. 2014; 8: 66-71Crossref PubMed Scopus (14) Google Scholar, Gruntz et al., 2018Gruntz K. Bloechliger M. Becker C. Jick S.S. Fuhr P. Meier C.R. Rüegg S. Parkinson disease and the risk of epileptic seizures.Ann. Neurol. 2018; 83: 363-374Crossref PubMed Scopus (33) Google Scholar), but little is known about the underlying mechanisms or if this is also the result of altered set points. It would therefore be interesting to use the technology from Styr et al., 2019Styr B. Gonen N. Zarhin D. Ruggiero A. Atsmon R. Gazit N. Braun G. Frere S. Vertkin I. Shapira I. et al.Mitochondrial regulation of the hippocampal firing rate set point and seizure susceptibility.Neuron. 2019; 102 (this issue): 1009-1024Scopus (50) Google Scholar to lower hyperexcitability early in these diseases and test whether this slows disease progression. Additional important open questions remain: what are the underlying molecular pathways of set-point regulation by mitochondrial DHODH, and what are the master regulators for homeostatic responses in neuronal networks? Identifying those will help in defining additional targets that can be manipulated to alter set-point regulation, as well as in the context of disease. Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure SusceptibilityStyr et al.NeuronApril 29, 2019In BriefFiring rate set-point regulation has puzzled researchers for decades. Our findings show that mitochondrial DHODH meets the criteria of a bone fide regulator of activity set points and suggest lowering firing set point as a new strategy to treat epilepsy. Full-Text PDF Open Access" @default.
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• W2948588876 title "Mitochondria Re-set Epilepsy" @default.
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