Daniel Reyes-Haro

Background: The cerebellum integrates sensory information to maintain balance and posture, allowing movement guidance. Perinatal damage to this brain region correlates with an increased incidence of Autism Spectrum Disorder (ASD), a major neurodevelopmental condition where poor motor performance in eye–hand coordination, balance and gait is observed. The cerebellum of ASD individuals is affected by reduced GABAergic signaling that leads to an excitatory/inhibitory imbalance. Methods: Motor coordination behavior were tested and Western blot essays performed to study the developmental expression of GABAergic signaling proteins, namely GABA_A receptor (α1, α2 and β1) subunits and glutamate decarboxylase 67 (GAD67), in CD1 mice prenatally exposed to valproic acid (VPA), a preclinical model of ASD. Results: The VPA group exhibited motor coordination deficits on postnatal day 30 (P30) compared to the control. The expression profiles for the control group revealed that GABA_A-α1 increased linearly, while GABA_A-β1 displayed the opposite pattern and GABA_A-α2 presented one peak of expression (P8). GAD67 decreased from embryonic day 16 (E16) to P8 but increased linearly after the first week of postnatal development (P8-P30). The developmental expression profile for all these proteins was disrupted by prenatal exposure to VPA. Conclusions: Motor coordination deficits correlate with a downregulated expression of GABA_A (α1, α2 and β1) subunits and GAD67 through cerebellar development in individuals that were prenatally exposed to VPA.

Background: Short-chain fatty acids (SCFAs) are metabolites produced by the gut microbiota after fiber fermentation. Some SCFAs, such as acetate, propionate, and butyrate, have been recognized as essential for human health, especially for the brain; however, the cellular mechanisms activated by these molecules in food-intake-related organs, such as the olfactory bulb, remain unclear. Objective: This study evaluates the effects of acetic acid (AA) and sodium butyrate on the physiology of Ca²⁺ metabolism in olfactory bulb cells (OBCs). Methods: Primary OBC cultures of the postnatal rat (P7-21) were made, and Ca²⁺ imaging experiments were performed to record the intracellular Ca²⁺ responses (iCaR) elicited by the application of AA and sodium butyrate (100 nM–1 mM). Immunocytochemical analyses were performed to identify GFAP⁺ cells and GPR41 and GPR43 receptors in OBCs. Endpoint RT-PCR analyses were made to identify GPR41 and GPR43 transcripts in OBCs. Results: Fewer than 10% of the OBCs tested responded to the application of AA and sodium butyrate with iCaR. Pharmacological studies (20 µM 2-aminoethyl diphenylborinate (2-APB); 10 nM GLPG0974, 120 nM AR420626) showed that iCaR were independent of inositol triphosphate (IP₃)-signaling pathways and that OBCs expressed both GPR41 and GPR43 receptors. Endpoint RT-PCR studies performed in both olfactory bulbs and primary OBC cultures confirmed the expression of the GPR41 receptor. Conclusions: This study shows that AA and butyrate induce intracellular Ca²⁺ responses activated by GPR41 and GPR43 receptors in a discrete cellular population of the rat olfactory bulb.

Autism spectrum disorder (ASD) is known as a group of neurodevelopmental conditions including stereotyped and repetitive behaviors, besides social and sensorimotor deficits. Anatomical and functional evidence indicates atypical maturation of the striatum. Astrocytes regulate the maturation and plasticity of synaptic circuits, and impaired calcium signaling is associated with repetitive behaviors and atypical social interaction. Spontaneous calcium transients (SCT) recorded in the striatal astrocytes of the rat were investigated in the preclinical model of ASD by prenatal exposure to valproic acid (VPA). Our results showed sensorimotor delay, augmented glial fibrillary acidic protein -a typical intermediate filament protein expressed by astrocytes- and diminished expression of GABA_A-ρ3 through development, and increased frequency of SCT with a reduced latency that resulted in a diminished amplitude in the VPA model. The convulsant picrotoxin, a GABA_A (γ-aminobutyric acid type A) receptor antagonist, reduced the frequency of SCT in both experimental groups but rescued this parameter to control levels in the preclinical ASD model. The amplitude and latency of SCT were decreased by picrotoxin in both experimental groups. Nipecotic acid, a GABA uptake inhibitor, reduced the mean amplitude only for the control group. Nevertheless, nipecotic acid increased the frequency but diminished the latency in both experimental groups. Thus, we conclude that striatal astrocytes exhibit SCT modulated by GABA_A-mediated signaling, and prenatal exposure to VPA disturbs this tuning.

Gamma-aminobutyric acid (GABA) is known as the main inhibitory transmitter in the central nervous system (CNS), where it hyperpolarizes mature neurons through activation of GABA_A receptors, pentameric complexes assembled by combination of subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π and ρ1–3). GABA_A-ρ subunits were originally described in the retina where they generate non-desensitizing Cl- currents that are insensitive to bicuculline and baclofen. However, now is known that they are widely expressed throughout the brain including glial cells. For example, whole-cell patch-clamp recordings demonstrated the functional expression of GABA_A-ρ receptors in primary cultures of cerebellar astrocytes, as well as in cerebellar ependymal cells and striatal astrocytes. In these cells GABA-currents were partially blocked by TPMPA and insensitive to barbiturates. These receptors are proposed to be involved in extrasynaptic communication and dysfunction of the signaling is accompanied by reduced expression of GABA_A-ρ receptors in Huntington’s disease and autism spectrum disorders (ASD). Thus, the aim of this review is to present an overview about GABA_A-ρ receptors including their structure and function, as well as their importance in the excitatory/inhibitory (E/I) balance in neurodevelopment and in disease.

Editorial: Physiology and pathology of neuroglia

Anorexia is a loss of appetite or an inability to eat and is often associated with eating disorders. However, animal anorexia is physiologically regulated as a part of the life cycle; for instance, during hibernation, migration or incubation. Anorexia nervosa (AN), on the other hand, is a common eating disorder among adolescent females that experience an intense fear of gaining weight due to body image distortion that results in voluntary avoidance of food intake and, thus, severe weight loss. It has been shown that the neurobiology of feeding extends beyond the hypothalamus. The prefrontal cortex (PFC) is involved in food choice and body image perception, both relevant in AN. However, little is known about the neurobiology of AN, and the lack of effective treatments justifies the use of animal models. Glial cells, the dominant population of nerve cells in the central nervous system, are key in maintaining brain homeostasis. Accordingly, recent studies suggest that glial function may be compromised by anorexia. In this review, we summarize recent findings about anorexia and glial cells.

En el siglo pasado se consideraba que los ensambles neuronales representaban el único sustrato de cognición. Las neuronas se identifican como células nerviosas excitables que tienen la habilidad de producir potenciales de acción, lo que promueve la liberación de neurotransmisores y la conectividad sináptica. Sin embargo, dado que la neuroglía es el grupo de células nerviosas dominantes y estas no producen potenciales de acción, se pensaba que no eran excitables y que su función se restringía a regular la homeostasis del cerebro. La neuroglía agrupa a la astroglía, la oligodendroglía y la microglía; todas expresan canales iónicos, transportadores y receptores a neurotransmisores, lo que les permite responder a los cambios que ocurren en el ambiente sináptico y extrasináptico. Las respuestas gliales incluyen fluctuaciones iónicas transitorias, así como la señalización intracelular de segundos mensajeros, lo que promueve la liberación de gliotransmisores y resulta en la modulación de la actividad neuronal. En conjunto, estos eventos definen lo que es la excitabilidad glial y su disfunción comienza a documentarse en distintas neuropatologías.

Autism spectrum disorders (ASD) are pervasive neurodevelopmental conditions detected during childhood when delayed language onset and social deficits are observed. Children diagnosed with ASD frequently display sensorimotor deficits associated with the cerebellum, suggesting a dysfunction of synaptic circuits. Astroglia are part of the tripartite synapses and postmortem studies reported an increased expression of the glial fibrillary acidic protein (GFAP) in the cerebellum of ASD patients. Astroglia respond to neuronal activity with calcium transients that propagate to neighboring cells, resulting in a functional response known as a calcium wave. This form of intercellular signaling is implicated in proliferation, migration, and differentiation of neural precursors. Prenatal exposure to valproate (VPA) is a preclinical model of ASD in which premature migration and excess of apoptosis occur in the internal granular layer (IGL) of the cerebellum during the early postnatal period. In this study we tested calcium wave propagation in the IGL of mice prenatally exposed to VPA. Sensorimotor deficits were observed and IGL depolarization evoked a calcium wave with astrocyte recruitment. The calcium wave propagation, initial cell recruitment, and mean amplitude of the calcium transients increased significantly in VPA-exposed mice compared to the control group. Astrocyte recruitment was significantly increased in the VPA model, but the mean amplitude of the calcium transients was unchanged. Western blot and histological studies revealed an increased expression of GFAP, higher astroglial density and augmented morphological complexity. We conclude that the functional signature of the IGL is remarkably augmented in the preclinical model of autism.