Astrocytes Regulate Inhibitory Synapse Formation via Trk-Mediated Modulation of Postsynaptic GABA_AReceptors

Abstract

Astrocytes promote the formation and function of excitatory synapses in the CNS. However, whether and how astrocytes modulate inhibitory synaptogenesis are essentially unknown. We asked whether astrocytes regulate the formation of inhibitory synapses between hippocampal neurons during maturation in vitro. Neuronal coculture with astrocytes or treatment with astrocyte-conditioned medium (ACM) increased the number of inhibitory presynaptic terminals, the frequency of miniature IPSCs, and the number and synaptic localization of GABA A receptor (GABA A R) clusters during the first 10 d in vitro. We asked whether neurotrophins, which are potent modulators of inhibitory synaptic structure and function, mediate the effects of astrocytes on inhibitory synapses. ACM from BDNF-or tyrosine receptor kinase B (TrkB)-deficient astrocytes increased inhibitory presynaptic terminals and postsynaptic GABA A R clusters in wild-type neurons, suggesting that BDNF and TrkB expression in astrocytes is not required for these effects. In contrast, although the increase in the number of inhibitory presynaptic terminals persisted, no increase was observed in postsynaptic GABA A R clusters after ACM treatment of hippocampal neurons lacking BDNF or TrkB. These results suggest that neurons, not astrocytes, are the relevant source of BDNF and are the site of TrkB activation required for postsynaptic GABA A R modulation. These data also suggest that astrocytes may modulate postsynaptic development indirectly by stimulating Trk signaling between neurons. Together, these data show that astrocytes modulate inhibitory synapse formation via distinct presynaptic and postsynaptic mechanisms.

Neurotrophin signaling among neurons and glia during formation of tripartite synapses

“…We showed that astrocytes enhance inhibitory synaptogenesis by promoting the formation and postsynaptic localization of GABA A R clusters via neurotrophin and Trk-mediated signaling (Elmariah et al, 2005). We found that astrocytes increase the number and synaptic localization of GABA A R clusters during the first week in vitro (Fig.…”

“…We also observe that NT 3 -mediated signaling decreases the synaptic localization of GABA A R clusters in the presence of astrocytes. Together, these results indicate that neurotrophin and Trk signaling are not required in astrocytes, but are required in neurons, to increase postsynaptic GABA A R clusters (Elmariah et al, 2005).…”

Conditional Knock-Out of Kir4.1 Leads to Glial Membrane Depolarization, Inhibition of Potassium and Glutamate Uptake, and Enhanced Short-Term Synaptic Potentiation

“…Reduction of astrocyte K ϩ and glutamate uptake observed in K ir 4.1 cKO hippocampus would therefore be expected to impair neuronal functioning. In addition, astrocyte-released neuroactive substances have been shown to affect neuronal excitability Tian et al, 2005), excitatory and inhibitory synaptic transmission and plasticity (Kang et al, 1998;Beattie et al, 2002;Yang et al, 2003;Fiacco and McCarthy, 2004;Pascual et al, 2005), as well as synaptogenesis and neuronal wiring (Collazos-Castro and NietoSampedro, 2001;Fasen et al, 2003;Ullian et al, 2004;Elmariah et al, 2005). Cell depolarization may impair astrocyte intracellular signaling and lead to changes in gliotransmitter release, thus affecting neuronal activity in a variety of ways.…”

GABABReceptor Activation Triggers BDNF Release and Promotes the Maturation of GABAergic Synapses

“…Thus, postsynaptic Ca 2ϩ elevation and ␣-CaMKII phosphorylation might underlie the GABA B -R-induced secretion of BDNF and development of GABAergic synapses that we found in the present study. Alternatively, GABA B -Rs can increase Ca 2ϩ concentration in glial cells (Kang et al, 1998;Meier et al, 2008) and indirectly trigger neuronal secretion of BDNF (Elmariah et al, 2005). Further experiments will be required to address this point.…”