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The Journal of Neuroscience, December 1, 2001, 21(23):9101-9111

Synaptojanin 1 Contributes to Maintaining the Stability of GABAergic Transmission in Primary Cultures of Cortical Neurons

Anita Lüthi¹, Gilbert Di Paolo², Ottavio Cremona³, Laurie Daniell², Pietro De Camilli², and David A. McCormick¹

¹ Section of Neurobiology, ² Department of Cell Biology and Howard Hughes Medical Institute, Yale University, School of Medicine, New Haven, Connecticut 06510, and ³ Dipartimento di Scienze Mediche, Università del Piemonte Orientale "A. Avogadro," Novara, Italy

Inhibitory synapses in the CNS can exhibit a considerable stability of neurotransmission over prolonged periods of high-frequency stimulation. Previously, we showed that synaptojanin 1 (SJ1), a presynaptic polyphosphoinositide phosphatase, is required for normal synaptic vesicle recycling (Cremona et al., 1999). We asked whether the stability of inhibitory synaptic responses was dependent on SJ1. Whole-cell patch-clamp recordings of unitary IPSCs were obtained in primary cortical cultures between cell pairs containing a presynaptic, fast-spiking inhibitory neuron (33.5-35°C). Prolonged presynaptic stimulation (1000 stimuli, 2-20 Hz) evoked postsynaptic responses that decreased in size with a bi-exponential time course. A fast component developed within a few stimuli and was quantified with paired-pulse protocols. Paired-pulse depression (PPD) appeared to be independent of previous GABA release at intervals of 100 msec. The characteristics of PPD, and synaptic depression induced within the first ~80 stimuli in the trains, were unaltered in SJ1-deficient inhibitory synapses.

A slow component of depression developed within hundreds of stimuli, and steady-state depression showed a sigmoidal dependence on stimulation frequency, with half-maximal depression at 6.0 ± 0.5 Hz. Slow depression was increased when release probability was augmented, and there was a small negative correlation between consecutive synaptic amplitudes during steady-state depression, consistent with a presynaptic depletion process. Slow depression was increased in SJ1-deficient synapses, with half-maximal depression at 3.3 ± 0.9 Hz, and the recovery was retarded ~3.6-fold. Our studies establish a link between a distinct kinetic component of physiologically monitored synaptic depression and a molecular modification known to affect synaptic vesicle reformation.

Key words: inhibitory synaptic transmission; synaptic depression; short-term plasticity; vesicle recycling; clathrin-mediated endocytosis; synaptojanin; phosphoinositide metabolism

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21239101-11$05.00/0

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