Neuroestradiol and neuronal development: Not an exclusive male tale anymore.

The brain synthesizes a variety of neurosteroids, including neuroestradiol. Inhibition of neuroestradiol synthesis results in alterations in basic neurodevelopmental processes, such as neurogenesis, neuroblast migration, neuritogenesis and synaptogenesis. Although the neurodevelopmental actions of neuroestradiol are exerted in both sexes, some of them are sex-specific, such as the well characterized effects of neuroestradiol derived from the metabolism of testicular testosterone during critical periods of male brain development. In addition, recent findings have shown sex-specific actions of neuroestradiol on neuroblast migration, neuritic growth and synaptogenesis in females. Among other factors, the epigenetic regulation exerted by X linked genes, such as Kdm6a/Utx, may determine sex-specific actions of neuroestradiol in the female brain. This review evidences the impact of neuroestradiol on brain formation in both sexes and highlights the interaction of neural steriodogenesis, hormones and sex chromosomes in sex-specific brain development.

Detection and genotyping of zoonotic microsporidia in the endangered Iberian lynx (Lynx pardinus).

Microsporidia is a diverse group of obligate, intracellular, and spore-forming parasites that infect a wide range of animals. Among them, Enterocytozoon bieneusi and Encephalitozoon spp. are the most frequently reported species in humans. Limited information is available about the presence and molecular diversity of microsporidian species in the endangered Iberian lynx (Lynx pardinus). Presence of Enterocytozoon bieneusi and Encephalitozoon spp. was investigated by molecular methods in wild and captive Iberian lynxes from Spain. Overall, E. bieneusi was detected in 3.2% (8/251) of the animals examined. None of the samples tested were positive for Encephalitozoon spp. Four known (D, EbfelA, PigEBITS7, and Type IV) and a novel (named as LynxSpEb1) E. bieneusi genotypes were identified. All the genotypes found belonged to the zoonotic Group 1 of E. bieneusi. This study provides the first genotyping data of E. bieneusi in Iberian lynx in Spain. Our result indicate that the Iberian lynx does not seem to play a relevant role in the epidemiology of Encephalitozoon spp., and that this endangered felid is likely acting as spillover host rather than a true reservoir of E. bieneusi. Additional studies should be conducted to assess the impact of this parasite in the health status of the endangered Iberian lynx.

Insulin-like growth factor I mitigates post-traumatic stress by inhibiting AMP-kinase in orexin neurons.

Maladaptive coping behaviors are probably involved in post-traumatic stress disorders (PTSD), but underlying mechanisms are incompletely understood. We now report that mice lacking functional insulin-like growth factor I (IGF-I) receptors in orexin neurons of the lateral hypothalamus (Firoc mice) are unresponsive to the anxiolytic actions of IGF-I and develop PTSD-like behavior that is ameliorated by inhibition of orexin neurons. Conversely, systemic IGF-I treatment ameliorated PTSD-like behavior in a wild-type mouse model of PTSD (PTSD mice). Further, systemic IGF-I modified the GABA/Glutamate synaptic structure in orexin neurons of naïve wild-type mice by increasing the dephosphorylation of GABA(B) receptor subunit through inhibition of AMP-kinase (AMPK). Significantly, pharmacological inhibition of AMPK mimicked IGF-I, normalizing fear behavior in PTSD mice. Thus, we suggest that IGF-I enables coping behaviors by balancing E/I input onto orexin neurons in a context-dependent manner. These observations provide a novel therapeutic approach to PTSD through modulation of AMPK.

Bis(bipyridine)ruthenium(II) Ferrocenyl ß-Diketonate Complexes: Exhibiting Nanomolar Potency against Human Cancer Cell Lines.

The synthesis and characterization of new bis(bipyridine)ruthenium(II) ferrocenyl ß-diketonate complexes, [(bpy)2 Ru(Fc-acac)][PF6 ] (bpy=2,2'-bipyridine; Fc-acac=functionalized ferrocenyl ß-diketonate ligand) are reported. Alongside clinical platinum drugs, these bimetallic ruthenium-iron complexes have been screened for their cytotoxicity against MIA PaCa-2 (human pancreatic carcinoma), HCT116 p53+/+ (human colon carcinoma, p53-wild type) and ARPE-19 (human retinal pigment epithelial) cell lines. With the exception of one complex, the library exhibit nanomolar potency against cancerous cell lines, and their relative potencies are up to 40x, 400x and 72x more cytotoxic than cisplatin, carboplatin and oxaliplatin, respectively. Under hypoxic conditions, the complexes remain cytotoxic (sub-micromolar range), highlighting their potential in targeting hypoxic tumor regions. The Comet assay was used to determine their ability to damage DNA, and results show dose dependent damage which correlates well with the cytotoxicity results. Their potential to treat bacterial and fungal strains has been determined, and highlight complexes have selective growth inhibition of up to 87-100 % against Staphylococcus aureus and Candida albicans.

Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation.

Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. We find that learning-related activity patterns known to induce N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation and transient optogenetic activation of single neurons induce within hours a robust increase in the formation and size of gephyrin-tagged clusters at inhibitory synapses identified by correlated confocal electron microscopy. This inhibitory morphological plasticity was associated with an increase in spontaneous inhibitory activity but did not require activation of GABAA receptors. Importantly, this activity-dependent inhibitory plasticity was prevented by pharmacological blockade of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), it was associated with an increased phosphorylation of gephyrin on a site targeted by CaMKII, and could be prevented or mimicked by gephyrin phospho-mutants for this site. These results reveal a homeostatic mechanism through which activity regulates the dynamics and function of perisomatic inhibitory synapses, and they identify a CaMKII-dependent phosphorylation site on gephyrin as critically important for this process.

Nitric oxide mediates local activity-dependent excitatory synapse development.

Learning related paradigms play an important role in shaping the development and specificity of synaptic networks, notably by regulating mechanisms of spine growth and pruning. The molecular events underlying these synaptic rearrangements remain poorly understood. Here we identify NO signaling as a key mediator of activity-dependent excitatory synapse development. We find that chronic blockade of NO production in vitro and in vivo interferes with the development of hippocampal and cortical excitatory spine synapses. The effect results from a selective loss of activity-mediated spine growth mechanisms and is associated with morphological and functional alterations of remaining synapses. These effects of NO are mediated by a cGMP cascade and can be reproduced or prevented by postsynaptic expression of vasodilator-stimulated phosphoprotein phospho-mimetic or phospho-resistant mutants. In vivo analyses show that absence of NO prevents the increase in excitatory synapse density induced by environmental enrichment and interferes with the formation of local clusters of excitatory synapses. We conclude that NO plays an important role in regulating the development of excitatory synapses by promoting local activity-dependent spine-growth mechanisms.

Deep dry needling of trigger points located in the lateral pterygoid muscle: Efficacy and safety of treatment for management of myofascial pain and temporomandibular dysfunction.

BACKGROUND: To determine whether deep dry needling (DDN) of trigger points (TPs) in the lateral pterygoid muscle (LPM) would significantly reduce pain and improve function, compared with methocarbamol/paracetamol medication. MATERIAL AND METHODS: Forty-eight patients with chronic myofascial pain located in the LPM were selected and randomly assigned to one of two groups (DDN test group, n=24; drug-treated control group, n=24). The test group received three applications of needling of the LPM once per week for three weeks, while control group patients were given two tablets of a methocarbamol/paracetamol combination every six hours for three weeks. Assessments were carried out pre-treatment, 2 and 8 weeks after finishing the treatment. RESULTS: A statistically significant difference (p<0.05) was detected for both groups with respect to pain reduction at rest and with mastication, but the DDN test group had significantly better levels of pain reduction. Moreover, statistically significant differences (p<0.05) up to day 70 in the test group were seen with respect to maximum mouth opening, laterality and protrusion movements compared with pre-treatment values. Pain reduction in the test group was greater as a function of pain intensity at baseline. The evaluation of efficacy as assessed both by patients/investigators was better for the test group. 41% of the patients receiving the combination drug treatment described unpleasant side effects (mostly drowsiness). CONCLUSIONS: DDN of TPs in the LPM showed better efficacy in reducing pain and improving maximum mouth opening, laterality, and protrusion movements compared with methocarbamol/paracetamol treatment. No adverse events were observed with respect to DDN.

Reversal of activity-mediated spine dynamics and learning impairment in a mouse model of Fragile X syndrome.

Fragile X syndrome (FXS) is characterized by intellectual disability and autistic traits, and results from the silencing of the FMR1 gene coding for a protein implicated in the regulation of protein synthesis at synapses. The lack of functional Fragile X mental retardation protein has been proposed to result in an excessive signaling of synaptic metabotropic glutamate receptors, leading to alterations of synapse maturation and plasticity. It remains, however, unclear how mechanisms of activity-dependent spine dynamics are affected in Fmr knockout (Fmr1-KO) mice and whether they can be reversed. Here we used a repetitive imaging approach in hippocampal slice cultures to investigate properties of structural plasticity and their modulation by signaling pathways. We found that basal spine turnover was significantly reduced in Fmr1-KO mice, but markedly enhanced by activity. Additionally, activity-mediated spine stabilization was lost in Fmr1-KO mice. Application of the metabotropic glutamate receptor antagonist α-Methyl-4-carboxyphenylglycine (MCPG) enhanced basal turnover, improved spine stability, but failed to reinstate activity-mediated spine stabilization. In contrast, enhancing phosphoinositide-3 kinase (PI3K) signaling, a pathway implicated in various aspects of synaptic plasticity, reversed both basal turnover and activity-mediated spine stabilization. It also restored defective long-term potentiation mechanisms in slices and improved reversal learning in Fmr1-KO mice. These results suggest that modulation of PI3K signaling could contribute to improve the cognitive deficits associated with FXS.

Detection and Molecular Diversity of Cryptosporidium spp. and Giardia duodenalis in the Endangered Iberian Lynx (Lynx pardinus), Spain.

Cryptosporidium spp. and Giardia duodenalis are the main non-viral causes of diarrhoea in humans and domestic animals globally. Comparatively, much less information is currently available in free-ranging carnivore species in general and in the endangered Iberian lynx (Lynx pardinus) in particular. Cryptosporidium spp. and G. duodenalis were investigated with molecular (PCR and Sanger sequencing) methods in individual faecal DNA samples of free-ranging and captive Iberian lynxes from the main population nuclei in Spain. Overall, Cryptosporidium spp. and G. duodenalis were detected in 2.4% (6/251) and 27.9% (70/251) of the animals examined, respectively. Positive animals to at least one of them were detected in each of the analysed population nuclei. The analysis of partial ssu rRNA gene sequences revealed the presence of rodent-adapted C. alticolis (n = 1) and C. occultus (n = 1), leporid-adapted C. cuniculus (n = 2), and zoonotic C. parvum (n = 2) within Cryptosporidium, and zoonotic assemblages A (n = 5) and B (n = 3) within G. duodenalis. Subgenotyping analyses allowed for the identification of genotype VaA19 in C. cuniculus (gp60 locus) and sub-assemblages AI and BIII/BIV in G. duodenalis (gdh, bg, and tpi loci). This study represents the first molecular description of Cryptosporidium spp. and G. duodenalis in the Iberian lynx in Spain. The presence of rodent/leporid-adapted Cryptosporidium species in the surveyed animals suggests spurious infections associated to the Iberian lynx's diet. The Iberian lynx seems a suitable host for zoonotic genetic variants of Cryptosporidium (C. parvum) and G. duodenalis (assemblages A and B), although the potential risk of human transmission is regarded as limited due to light parasite burdens and suspected low excretion of infective (oo)cysts to the environment by infected animals. More research should be conducted to ascertain the true impact of these protozoan parasites in the health status of the endangered Iberian lynx.

Direct alteration of a specific inhibitory circuit of the hippocampus by antidepressants.

Correct brain functioning relies on the precise activity of a myriad of synapses assembling neurons in complex networks. In the hippocampus, highly diverse inhibitory circuits differently govern several physiologically relevant network activities. Particularly, perisomatic inhibition provided by specific interneurons was proposed to control emotional states, and could therefore be affected by mood disorders and their therapy. We found that both chronic and acute administration of two major antidepressants, imipramine and fluoxetine, strongly and directly altered GABA-mediated (GABAergic) hippocampal neurotransmission in mice and rats, independently of their effects on amine reuptake systems. These drugs affected GABA release from synapses formed by fast-spiking cells, but not interneurons expressing cannabinoid receptor type 1, resulting in the disruption of γ oscillations. This differential effect, shared by two types of antidepressants, suggests a new mechanism of action of these medications, and a possible role of perisomatic inhibition in depressive disorders.

Desynchronization of neocortical networks by asynchronous release of GABA at autaptic and synaptic contacts from fast-spiking interneurons.

Networks of specific inhibitory interneurons regulate principal cell firing in several forms of neocortical activity. Fast-spiking (FS) interneurons are potently self-inhibited by GABAergic autaptic transmission, allowing them to precisely control their own firing dynamics and timing. Here we show that in FS interneurons, high-frequency trains of action potentials can generate a delayed and prolonged GABAergic self-inhibition due to sustained asynchronous release at FS-cell autapses. Asynchronous release of GABA is simultaneously recorded in connected pyramidal (P) neurons. Asynchronous and synchronous autaptic release show differential presynaptic Ca(2+) sensitivity, suggesting that they rely on different Ca(2+) sensors and/or involve distinct pools of vesicles. In addition, asynchronous release is modulated by the endogenous Ca(2+) buffer parvalbumin. Functionally, asynchronous release decreases FS-cell spike reliability and reduces the ability of P neurons to integrate incoming stimuli into precise firing. Since each FS cell contacts many P neurons, asynchronous release from a single interneuron may desynchronize a large portion of the local network and disrupt cortical information processing.

Protein Kinase A-Dependent Plasticity of Local Inhibitory Synapses from Hilar Somatostatin-Expressing Neurons.

Hippocampal inhibitory neurons (INs) contact local targets and project to different brain areas to form synapses on distal neurons. Despite the importance of INs for hippocampal function and interregional brain communication, the impact of activity-dependent plasticity mechanisms on local and long-range GABAergic synapses formed by hippocampal INs remains to be fully elucidated. Here, we use optogenetic-coupled electrophysiology in mice to show that protein kinase A (PKA), a master regulator of GABAergic synapse plasticity, causes a form of long-term potentiation of inhibitory synapses (iLTP) in hippocampal granule cells (GCs). This form of iLTP is observed in GCs synapses originated in local INs expressing the marker somatostatin (SST), but not in those expressing parvalbumin. Long-range synapses formed by SST INs onto medial septum neurons are unaffected by PKA activation. iLTP of local SST synapses on GCs is accompanied by changes in presynaptic probability of release and is occluded by pharmacological increase of synaptic activity in vivo Our results suggest that PKA-dependent inhibitory synapse plasticity is expressed in local, but not long-range, targets of SST INs and selectively modifies inhibitory microcircuits essential for hippocampal function.

Occurrence of Leishmania infantum in Wild Mammals Admitted to Recovery Centers in Spain.

Zoonotic leishmaniasis caused by Leishmania infantum is distributed worldwide and affects humans and domestic and wild mammals. In Europe, specifically in the Mediterranean basin, leishmaniasis is endemic due to the concurrence of the phlebotomine vectors and reservoir mammals, including carnivorous wildlife species and other less studied wild species. In this article, spleen, skin, and eye or oral swabs taken from 134 wild mammals admitted to five wildlife recovery centers in Spain were used. PCR employing fragments of the Repeat region, ITS1, and SSUrRNA were used for detection, and positive samples were processed for sequencing. L. infantum was detected in three out of the nine species analyzed, including European hedgehog, European badger, and red squirrel, with percentages ranging from 11.53 to 35.71%, depending on the species. Most of the species showed higher percentages of positivity in spleen samples than in skin samples. A small number of animals from the remaining six species tested negative, including Algerian hedgehog, stone marten, least weasel, garden dormouse, western polecat, and Egyptian mongoose. Hedgehogs and badgers are good candidates for consideration as epidemiological sentinels and pose a higher risk as potential reservoirs of leishmaniasis based on their percentage of infection and wide distribution.

Prevalence of Toxoplasma gondii in Endangered Wild Felines (Felis silvestris and Lynx pardinus) in Spain.

The wildcat (Felis silvestris) and the Iberian lynx (Lynx pardinus) are important species in Spain, considered as near-threatened and endangered, respectively. Both can be infected by Toxoplasma gondii, a parasite that can cause morbidity and mortality in transplacentally-infected or immunocompromised mammals. The data on the prevalence of this parasite in wild populations of these species in Spain are outdated. The objective of this study was to update information and evaluate the role of these felines in parasite epidemiology and the potential impact of the parasite on their conservation. Blood and fecal samples were collected from captured animals, as well as the tongue, diaphragm, and spleen, from animals killed in road accidents in central Spain. An indirect fluorescent antibody test (IFAT) was used to detect parasite antibodies in serum, microscopy and molecular analysis were used to detect oocysts in feces, and molecular analysis was used to determine the existence of tissue cysts. Seroprevalence was 85% in wildcats and 45% in lynx, and parasite DNA was detected in the feces of one wildcat and in tissue samples from 10 wildcats and 11 Iberian lynxes. These results highlight the epidemiological importance and high risk of T. gondii infection in animals and humans in the studied areas. Considering feline susceptibility to infection, monitoring programs are needed to assess the health status of wild felines.

Cytotoxicity of Ruthenium(II) Arene Complexes Containing Functionalized Ferrocenyl ß-Diketonate Ligands.

The synthesis and characterization of 24 ruthenium(II) arene complexes of the type [(p-cym)RuCl(Fc-acac)] (where p-cym = p-cymene and Fc-acac = functionalized ferrocenyl ß-diketonate ligands) are reported, including single-crystal X-ray diffraction for 21 new complexes. Chemosensitivity studies have been conducted against human pancreatic carcinoma (MIA PaCa-2), human colorectal adenocarcinoma p53-wildtype (HCT116 p53+/+) and normal human retinal epithelial cell lines (APRE-19). The most active complex, which contains a 2-furan-substituted ligand (4), is 5x more cytotoxic than the analogs 3-furan complex (5) against MIA PaCa-2. Several complexes were screened under hypoxic conditions and at shorter-time incubations, and their ability to damage DNA was determined by the comet assay. Compounds were also screened for their potential to inhibit the growth of both bacterial and fungal strains.

OCT-Angiography Changes in Patients with Diabetic Macular Edema Treated with Intravitreal Dexamethasone Implant.

PURPOSE: To evaluate, using optical coherence tomography angiography (OCTA), the impact of intravitreal dexamethasone (DEX) implant on quantitative vascular measurements in patients with diabetic macular edema (DME). METHODS: Prospective, randomized, and open-label study. Primary endpoints were mean changes in vessel density (VD) and vascular perfusion (VP) in superficial capillary plexus (SCP) and VP in deep capillary plexus (DCP) and peripapillary capillary plexus (PCP). RESULTS: Thirty-four eyes from 19 patients were included. Mean age was 67.4±7.3 years and 24 (76.5%) were men. VD in SCP in the 6 mm × 6 mm perifoveal ring was significantly decreased from 15.2±2.7 mm/mm2 at baseline to 13.5±3.1 at month-2, p, 0.0029. VP in SCP in the 6 mm × 6 mm perifoveal ring decreased significantly from baseline to month-2 (mean change -3.8%; 95% confidence-interval: -7.7% to -1.7%, p, 0.0028). Compared to baseline, the VP in DCP was significantly reduced at month 2 in the perifoveal ring of the 6 mm × 6 mm scan (p, 0.0063), and in the parafoveal ring of the 6 mm × 6 mm scan (p, 0.0048). Foveal avascular zone (FAZ) area did not change throughout the study. Central macular thickness significantly decreased from baseline in 210.3 µm (149.9-270.8 µm) and 201.8 µm (140.4-263.3 µm), p < 0.0001 each at month-2 and month-3, respectively. CONCLUSIONS: Besides functional and anatomical improvements, DEX implant significantly reduced VD and VP in DME patients.

A novel role for the lateral habenula in fear learning.

Fear is an extreme form of aversion that underlies pathological conditions such as panic or phobias. Fear conditioning (FC) is the best-understood model of fear learning. In FC the context and a cue are independently associated with a threatening unconditioned stimulus (US). The lateral habenula (LHb) is a general encoder of aversion. However, its role in fear learning remains poorly understood. Here we studied in rats the role of the LHb in FC using optogenetics and pharmacological tools. We found that inhibition or activation of the LHb during entire FC training impaired both cued and contextual FC. In contrast, optogenetic inhibition of the LHb restricted to cue and US presentation impaired cued but not contextual FC. In either case, simultaneous activation of contextual and cued components of FC, by the presentation of the cue in the training context, recovered the conditioned fear response. Our results support the notion that the LHb is required for the formation of independent contextual and cued fear memories, a previously uncharacterized function for this structure, that could be critical in fear generalization.

Sex-specific regulation of inhibition and network activity by local aromatase in the mouse hippocampus.

Cognitive function relies on a balanced interplay between excitatory and inhibitory neurons (INs), but the impact of estradiol on IN function is not fully understood. Here, we characterize the regulation of hippocampal INs by aromatase, the enzyme responsible for estradiol synthesis, using a combination of molecular, genetic, functional and behavioral tools. The results show that CA1 parvalbumin-expressing INs (PV-INs) contribute to brain estradiol synthesis. Brain aromatase regulates synaptic inhibition through a mechanism that involves modification of perineuronal nets enwrapping PV-INs. In the female brain, aromatase modulates PV-INs activity, the dynamics of network oscillations and hippocampal-dependent memory. Aromatase regulation of PV-INs and inhibitory synapses is determined by the gonads and independent of sex chromosomes. These results suggest PV-INs are mediators of estrogenic regulation of behaviorally-relevant activity.

[Respiratory physiotherapy in post-acute COVID-19 adult patients: Systematic review of literature]. / Fisioterapia respiratoria en pacientes adultos post-COVID-19: revisión sistemática de la literatura.

Background: Patients with SARS-CoV-2 present signs and symptoms that primarily involve the respiratory system. The sequelae result in impaired quality of life, pneumonia, dyspnea, fatigue, and joint pain. Objective: To sustain with scientific evidence the importance of respiratory physiotherapy and its effects on post-acute COVID-19 adult patients. Material and methods: A systematic review was conducted in four databases (Scopus, Web of Science, PubMed, and ScienceDirect). The searching period was carried out in February 2021 with a total of one 1229 potential studies. Finally, 5 studies that met the eligibility criteria were included: two clinical trials, two case reports and one cross-sectional study. The methodological quality of the articles was evaluated. Results: Respiratory muscle training, targeted breathing, and strength training provide significant data of improvement of functional performance. Evidence shows positive effects of respiratory physiotherapy in post-acute COVID-19 adult patients, since it increases resistance to exercise, it decreases fatigue, reduces dyspnea, improves functionality and quality of life. Conclusions: More future studies, such as randomized controlled trials, studies including lower age range groups, and individualized approaches, need to be developed.

Introducción: los pacientes con SARS-CoV-2 presentan signos y síntomas que involucran principalmente el sistema respiratorio. Las secuelas son consecuencia de un deterioro de la calidad de vida, neumonía, fatiga, disnea y dolor articular. Objetivo: tener el sustento científico que permita evidenciar la importancia de la fisioterapia respiratoria y sus efectos sobre los pacientes adultos post-COVID-19 de fase aguda. Material y métodos: se hizo una revisión sistemática de la literatura en cuatro bases de datos (Scopus, Web of Science, PubMed y ScienceDirect). La búsqueda fue realizada en febrero de 2021 con un total de 1229 estudios. Finalmente, se incluyeron cinco estudios que cumplieron con los criterios de elegibilidad: dos ensayos clínicos, dos reportes de caso y un estudio transversal. La calidad metodológica de las publicaciones fue evaluada. Resultados: el entrenamiento de la musculatura respiratoria, las respiraciones dirigidas y el fortalecimiento general dan datos significativos en la mejora de la funcionalidad. La evidencia demuestra que hay efectos positivos de la fisioterapia respiratoria en pacientes adultos post-COVID-19, pues aumenta la resistencia al ejercicio, disminuye la fatiga, se reduce la disnea, mejora la funcionalidad y la calidad de vida. Conclusiones: es necesario que se desarrollen más ensayos clínicos aleatorizados y estudios de grupos de menor rango de edad y con enfoques individualizados.

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.

Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.