Neurotrophin signaling among neurons and glia during formation of tripartite synapses

Abstract

Synapse formation in the CNS is a complex process that involves the dynamic interplay of numerous signals exchanged between pre-and postsynaptic neurons as well as perisynaptic glia. Members of the neurotrophin family, which are widely expressed in the developing and mature CNS and are wellknown for their roles in promoting neuronal survival and differentiation, have emerged as key synaptic modulators. However, the mechanisms by which neurotrophins modulate synapse formation and function are poorly understood. Here, we summarize our work on the role of neurotrophins in synaptogenesis in the CNS, in particular the role of these signaling molecules and their receptors, the Trks, in the development of excitatory and inhibitory hippocampal synapses. We discuss our results that demonstrate that postsynaptic TrkB signaling plays an important role in modulating the formation and maintenance of NMDA and GABAA receptor clusters at central synapses, and suggest that neurotrophin signaling coordinately modulates these receptors as part of mechanism that promotes the balance between excitation and inhibition in developing circuits. We also discuss our results that demonstrate that astrocytes promote the formation of GABAergic synapses in vitro by differentially regulating the development of inhibitory presynaptic terminals and postsynaptic GABAA receptor clusters, and suggest that glial modulation of inhibitory synaptogenesis is mediated by neurotrophin-dependent and -independent signaling. Together, these findings extend our understanding of how neuron-glia communication modulates synapse formation, maintenance and function, and set the stage for defining the cellular and molecular mechanisms by which neurotrophins and other cell-cell signals direct synaptogenesis in the developing brain.

Brain-derived Neurotrophic Factor (BDNF) Enhances GABA Transport by Modulating the Trafficking of GABA Transporter-1 (GAT-1) from the Plasma Membrane of Rat Cortical Astrocytes

“…These fast BDNF actions are synapse-specific, but the trend is toward a postsynaptic inhibition of GABAergic transmission, in particular toward an inhibition of inhibitory inputs to interneurons (46). The inhibitory action of BDNF disappears after prolonged exposure to BDNF (45), turning into a long lasting facilitatory action of GABA A responses, associated with an increase in GABA A receptor clusters (47). These long lasting effects of BDNF are more related to trophic than to fast signaling actions because they were shown to involve establishment of functional inhibitory synapses between interneurons (47).…”

SDF1α/CXCR4 Signaling, via ERKs and the Transcription Factor Egr1, Induces Expression of a 67-kDa Form of Glutamic Acid Decarboxylase in Embryonic Hippocampal Neurons

“…RNA Preparation and Reverse Transcriptase PCR Amplification-Total RNAs from rat E18 hippocampal cultures were isolated using RNA STAT-60 TM (Tel-Test, Inc). The cDNAs were synthesized using 1 g of total RNA in the presence of Superscript II and (dT) [12][13][14][15][16][17][18] (both from Invitrogen). The PCR was performed in a 20-l reaction solution containing 2 l of 10ϫ PCR buffer, 150 nmol of MgCl 2 , 10 nmol of dNTP, 20 pmol of primer, 1 l of10ϫ diluted cDNA, and 1 unit of RedTag DNA polymerase (Sigma).…”

Positive Feedback Regulation between γ-Aminobutyric Acid Type A (GABAA) Receptor Signaling and Brain-derived Neurotrophic Factor (BDNF) Release in Developing Neurons

“…Long term effects of BDNF during development are mediated by the activation of specific transcription factors, including cAMP response element-binding protein (CREB) (29). BDNF has been shown to modulate the efficacy of transmission at GABAergic synapses (33)(34)(35)(36) by regulating GABA A R phosphorylation (37,38) and cell surface expression (39 -42) and to promote GABAergic synaptogenesis (43)(44)(45)(46).…”