Impaired GABAB-mediated presynaptic inhibition increases excitatory strength and alters short-term plasticity in synapsin knockout mice
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Pierluigi Valente1,*, Pasqualina Farisello1,2,*, Flavia Valtorta3, Pietro Baldelli1,2 and Fabio Benfenati1,2
1Department of Experimental Medicine, Section of Physiology, University of Genoa, 16132 Genova, Italy
2Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, 16132 Genova, Italy
3S. Raffaele Scientific Institute and Vita-Salute University, 20132 Milano, Italy
*These authors have contributed equally to this work
Fabio Benfenati, email: firstname.lastname@example.org
Keywords: epilepsy, excitatory transmission, GABA receptors, facilitation, synaptic depression
Received: June 22, 2017 Accepted: September 03, 2017 Published: September 30, 2017
Synapsins are a family of synaptic vesicle phosphoproteins regulating synaptic transmission and plasticity. SYN1/2 genes are major epilepsy susceptibility genes in humans. Consistently, synapsin I/II/III triple knockout (TKO) mice are epileptic and exhibit severe impairments in phasic and tonic GABAergic inhibition that precede the appearance of the epileptic phenotype. These changes are associated with an increased strength of excitatory transmission that has never been mechanistically investigated. Here, we observed that an identical effect in excitatory transmission could be induced in wild-type (WT) Schaffer collateral-CA1 pyramidal cell synapses by blockade of GABAB receptors (GABABRs). The same treatment was virtually ineffective in TKO slices, suggesting that the increased strength of the excitatory transmission results from an impairment of GABAB presynaptic inhibition. Exogenous stimulation of GABABRs in excitatory autaptic neurons, where GABA spillover is negligible, demonstrated that GABABRs were effective in inhibiting excitatory transmission in both WT and TKO neurons. These results demonstrate that the decreased GABA release and spillover, previously observed in TKO hippocampal slices, removes the tonic brake of presynaptic GABABRs on glutamate transmission, making the excitation/inhibition imbalance stronger.
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