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The Journal of Neuroscience, April 6, 2005, 25(14):3638-3650; doi:10.1523/JNEUROSCI.3980-04.2005

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Development/Plasticity/Repair
Astrocytes Regulate Inhibitory Synapse Formation via Trk-Mediated Modulation of Postsynaptic GABA_A Receptors

Sarina B. Elmariah, Eun Joo Oh, Ethan G. Hughes, and Rita J. Balice-Gordon

Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

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_AR) 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_AR 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_AR 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_AR 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.

Key words: neurotrophin; BDNF; TrkB; GABA_A receptor; synapse formation; astrocyte

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Received Sep 25, 2004; revised February 24, 2005; accepted February 26, 2005.

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