ABSTRACT
CX3CR1 is a G protein-coupled receptor that is expressed exclusively by microglia within the brain parenchyma. The only known physiological CX3CR1 ligand is the chemokine fractalkine (FKN), which is constitutively expressed in neuronal cell membranes and tonically released by them. Through its key role in microglia-neuron communication, the FKN/CX3CR1 axis regulates microglial state, neuronal survival, synaptic plasticity, and a variety of synaptic functions, as well as neuronal excitability via cytokine release modulation, chemotaxis, and phagocytosis. Thus, the absence of CX3CR1 or any failure in the FKN/CX3CR1 axis has been linked to alterations in different brain functions, including changes in synaptic and network plasticity in structures such as the hippocampus, cortex, brainstem, and spinal cord. Since synaptic plasticity is a basic phenomenon in neural circuit integration and adjustment, here, we will review its modulation by the FKN/CX3CR1 axis in diverse brain circuits and its impact on brain function and adaptation in health and disease.
Subject(s)
Central Nervous System , Chemokine CX3CL1 , Chemokine CX3CL1/metabolism , CX3C Chemokine Receptor 1/metabolism , Microglia/metabolism , Spinal Cord/metabolismABSTRACT
Abstract: The present study describes the pharmacological analysis of the effects of carbachol, a cholinergic agonist, on hippocampal theta activity. Knowing that this activity is critically related to cognitive function and altered in patients with neurodegeneration, pharmacological efforts aiming to directly modulate hippocampal theta activity becomes of central importance. In a recently developed complete septo-hippocampal preparation, carbachol elicited significant theta power enhancement with 1 μM. Concentrations under 1 μM and over 2 μM carbachol caused significant reduction in the power of hippocampal theta activity. Carbachol effects were completely blocked with the cholinergic antagonist scopolamine. At the experimental level, it is the first time the direct action of a cholinergic agonist is evaluated in the septo-hippocampal pathway completely isolated. However, carbachol as a cholinergic agonist is a drug with a certain level of nonspecific response. That is why to correct this experimental limitation, we used scopolamine (cholinergic antagonist) which allowed us to corroborate the effects on the cholinergic pathway. In summary, electrophysiological assays demonstrated an effective concentration range of carbachol specifically modulating hippocampal theta activity.
Resumen: El presente estudio describe el análisis farmacológico de los efectos de carbacol, un agonista colinérgico, sobre la actividad theta del hipocampo. Sabiendo que esta actividad está críticamente relacionada con la función cognitiva y alterada en pacientes con neurodegeneración, los esfuerzos farmacológicos destinados a modular directamente la actividad theta del hipocampo se vuelven de gran importancia. En una preparación completa que contiene la región septal media conectada al hipocampo, desarrollada recientemente, 1 μM de carbacol provocó un incremento significativo a nivel de potencia en la actividad theta del hipocampo. Las concentraciones menores de1 μM y mayores a 2 μM causaron una reducción significativa en la potencia de la actividad theta. Los efectos del carbacol fueron completamente bloqueados con la escopolamina, antagonista colinérgico. A nivel experimental, es la primera vez que se evalúa la acción directa de un agonista colinérgico en la vía septo-hipocámpica completamente aislada. Sin embargo, el carbacol como agonista colinérgico es un fármaco que presenta cierto nivel de respuesta inespecífica. Es por eso que para corregir esta limitante experimental, se utilizó escopolamina (antagonista colinérgico) lo que nos permitió corroborar los efectos sobre la vía colinérgica. En resumen, nuestros estudios electrofisiológicos demostraron un intervalo de concentración eficaz del carbacol que modula específicamente la actividad theta del hipocampo.
ABSTRACT
Retinogenesis is a developmental process that involves the sequential formation of neurons and glia from retinal progenitors. Once retinogenesis is completed, Müller glial cells can be stimulated to differentiate into neuronal lineages and constitute a retina-intrinsic source of neural progenitors. The identification of the intrinsic and extrinsic factors that control proliferation and differentiation of Müller cells or retinal progenitors is needed in order to fully define their potential therapeutic use in regenerative approaches. Here we determined the response of retinal progenitors derived from Müller glia primary cell cultures to GABA-activated signal transduction cascades. Using Western blot analysis, immunocytochemistry and calcium imaging we found that GABA induces an increase of the number of progenitor cells that present spontaneous intracellular calcium transients as well as their frequency, which involve the participation of L-type voltage-gated calcium channels (VGCCs). This process correlates with the activation of transcription factor CREB through Ser33 phosphorylation and the induction of expression of the early neuronal markers NeuroD1 and ßIII-tubulin. GABA-mediated CREB phosphorylation was rapid and sustained and the pharmacological blockade of CREB activity inhibited the effect of GABA on NeuroD1 expression. Furthermore, consistent with the role of CREB as a histone acetyltransferase recruiter, we demonstrate that GABA induces the modification of histone H4 acetylation pattern in these cells suggesting that epigenetic alterations participate in the differentiation process. Our results support the notion that postnatal retinal progenitors derived from Müller glia primary cell cultures respond to GABA through the same molecular pathway previously characterized in hippocampal progenitors and developing neurons. We speculate that the induction of GABA receptor signaling could represent a novel strategy to enhance neural versus glial specification from these cells through genetic and epigenetic mechanisms.
