Octavio García

Increased mitochondrial respiration maintains the mitochondrial membrane potential and promotes survival of cerebellar neurons in an endogenous model of glutamate receptor activation

It is thought that the combination of extracellular glutamate accumulation and mitochondrial damage is involved in neuronal death associated with brain ischemia and hypoglycemia, and some neurodegenerative diseases such as Huntingtons disease. However, the mechanism whereby those two factors interact together to trigger neurodegeneration in this and other neurodegenerative disorders is still elusive. Here, we have addressed this issue using a model of mild and sustained accumulation of extracellular glutamate in cerebellar cultured neurons, which are mostly glutamatergic and commonly used to study glutamate neurotoxicity. The resulting stimulation of glutamate receptors triggered a ∼ 50% persistent increase in mitochondrial respiration that was associated with free radicals formation, and which was found to be necessary to prevent the collapse of the mitochondial membrane potential (Δψm) and apoptotic cell death. In fact, hampering the glutamate‐mediated increase in mitochondrial respiration with an inhibitor of the mitochondrial respiratory chain stopped neurons from producing free radicals, but led them to undergo rapid and profound Δψm collapse and apoptotic cell death. Thus, we suggest that the formation of reactive oxygen species by glutamate receptor activation is the unavoidable consequence of an increase in the mitochondrial respiration aimed to prevent Δψm collapse and neurodegeneration. These results may be relevant to understand the pathophysiology of those neurodegenerative diseases associated with both mitochondrial respiratory chain and glutamate transporter defects.

Glutamate uptake inhibitor L-trans-pyrrolidine 2,4-dicarboxylate becomes neurotoxic in the presence of subthreshold concentrations of mitochondrial toxin 3-nitropropionate: Involvement of mitochondrial reducing activity and ATP production

An increased concentration of extracellular glutamate is associated with neuronal damage induced by cerebral ischemia. We have demonstrated previously that exposure of cultured cerebellar granule neurons to L‐trans‐pyrrolidine‐2,4‐dicarboxylate (PDC), a glutamate uptake inhibitor, increases extracellular glutamate levels but does not induce neuronal damage. Coincubation of PDC, however, with a subthreshold concentration of the mitochondrial toxin, 3‐nitropropionic acid (3‐NP), results in severe damage to these neurons. We have investigated the time course of changes in mitochondrial reducing capacity and ATP levels in cerebellar granule cells after simultaneous exposure to 3‐NP and PDC, and its relation to cell viability and nuclear condensation. Although individually, 3‐NP and PDC treatments are not harmful to neurons, the simultaneous exposure to both compounds results in a progressive decline in mitochondrial reducing capacity during the first 4 hr, and a rapid decrease in ATP levels. At 4 hr, cells lose plasma membrane integrity and show condensed nuclei. In the presence of the energy substrates pyruvate and acetoacetate, the N‐methyl‐D‐apartate (NMDA) receptor antagonist, MK‐801, and the spin trapper α‐phenyl‐N‐tert‐butylnitrone (PBN), the decline in mitochondrial activity and ATP levels is prevented, the number of condensed nuclei is reduced, and plasma membrane integrity is preserved. In contrast, the broad‐spectrum caspase inhibitor Z‐Asp‐DCB (Z‐Asp‐CH2‐DCB) prevents nuclear condensation but has no effect on mitochondrial reducing capacity or cell survival. Our results show that glutamate uptake impairment rapidly induces neuronal death during inhibition of succinate dehydrogenase by a mechanism involving mitochondrial dysfunction that, if not prevented, leads to cell death.

Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome

Abnormal dendritic spine structure and function is one of the most prominent features associated with neurodevelopmental disorders including Down syndrome (DS). Defects in both spine morphology and spine density may underlie alterations in neuronal and synaptic plasticity, ultimately affecting cognitive ability. Here we briefly examine the role of astrocytes in spine alterations and more specifically the involvement of astrocyte-secreted thrombospondin 1 (TSP-1) deficits in spine and synaptic pathology in DS.

On the nonexistence of free complete distributive lattices

We prove that there is no free object over a countable set in the category of complete distributive lattices with homomorphisms preserving binary meets and arbitrary joins.

Alterations in neuronal cytoskeletal and astrocytic proteins content in the brain of the autistic-like mouse strain C58/J

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficient social interaction, impaired communication as well as repetitive behaviors. ASD subjects present connectivity and neuroplasticity disturbances associated with morphological alterations in axons, dendrites, and dendritic spines. Given that the neuronal cytoskeleton and astrocytes have an essential role in regulating several mechanisms of neural plasticity, the aim of this work was to study alterations in the content of neuronal cytoskeletal components actin and tubulin and their associated proteins, as well as astrocytic proteins GFAP and TSP-1 in the brain of a C58/J mouse model of ASD. We determined the expression and regulatory phosphorylation state of cytoskeletal components in the prefrontal cortex, hippocampus, and cerebellum of C58/J mice by means of Western blotting. Our results show that autistic-like mice present: 1) region-dependent altered expression and phosphorylation patterns of Tau isoforms, associated with anomalous microtubule depolymerization; 2) reduced MAP2 A content in prefrontal cortex; 3) region-dependent changes in cofilin expression and phosphorylation, associated with abnormal actin filament depolymerizing dynamics; 4) diminished synaptopodin levels in the hippocampus; and 5) reduced content of the astrocyte-secreted protein TSP-1 in the prefrontal cortex and hippocampus. Our work demonstrates changes in the expression and phosphorylation of cytoskeletal proteins as well as in TSP-1 in the brain of the autistic-like mice C58/J, shedding light in one of the possible molecular mechanisms underpinning neuroplasticity alterations in the ASD brain and laying the foundation for future investigations in this topic.

Vocabulary and Cognitive Flexibility in People with Down Syndrome

Background and rationale. Down syndrome (DS) is the most frequent genetic cause of intellectual disability in children and adults. Deficits in language comprehension and production, expressive language, verbal memory and cognitive flexibility (CF) are commonly described in individuals with DS. Nonetheless, their receptive vocabulary (RV) shows better development. Adolescents and adults with DS have deficits on CF which have an impact over linguistic skills. Research suggests a significant relationship between CF and RV in DS (Campbell et al. Am J Intellect Dev Disabil 118(3):193–200, 2013; Landry et al. J Dev Disabil 18(2):24–33, 2012). However, little is known regarding the factors involved in such relationship. The aim of this research, is to analyze such relationship.