Abstract
Classical electron microscopic studies of the mammalian brain revealed two major classes of synapses, distinguished by the presence of a large postsynaptic density (PSD) exclusively at type 1, excitatory synapses. Biochemical studies of the PSD have established the paradigm of the synapse as a complex signal-processing machine that controls synaptic plasticity. We report here the results of a proteomic analysis of type 2, inhibitory synaptic complexes isolated by affinity purification from the cerebral cortex. We show that these synaptic complexes contain a variety of neurotransmitter receptors, neural cell-scaffolding and adhesion molecules, but that they are entirely lacking in cell signaling proteins. This fundamental distinction between the functions of type 1 and type 2 synapses in the nervous system has far reaching implications for models of synaptic plasticity, rapid adaptations in neural circuits, and homeostatic mechanisms controlling the balance of excitation and inhibition in the mature brain.
Highlights
Type 1 synapses, which were identified over fifty years ago [1,2], mediate excitatory neurotransmission primarily through glutamate
In accordance with published methods [45], we found that 0.1% beta-octylglucopyranoside (b-OG) efficiently solubilized inhibitory receptors, but failed to enrich the inhibitory synaptic complex in high molecular weight fractions via gel filtration (Figure S1C). 3[3-cholamidopropyl-dimethylammonio]-l-propanesulfonate (CHAPS) solubilized GABAA receptors [45,46,47], and inhibitory synaptic complexes solubilized in 0.5% CHAPS were enriched in high molecular weight fractions (Figure S1A)
Functional and biochemical studies of type 1 excitatory synapses have established the current paradigm of the synapse as a complex subcellular machine that upon binding of neurotransmitters to receptors located on the postsynaptic membrane, regulates the influx of Na+ that triggers the depolarization of that cell, and transduces local Ca2+ influx into a wide variety of signals that are critical for synaptic plasticity, learning and memory [3,6,62]
Summary
Type 1 synapses, which were identified over fifty years ago [1,2], mediate excitatory neurotransmission primarily through glutamate. Over the past several decades, a multitude of studies [3,4,5,6] have identified the various components of the PSD These include scaffolding proteins, such as PSD-95 [7], which provide a central docking station for neurotransmitter receptors and ion channels, and signaling components such as Ca++/ calmodulin-dependent protein kinase II (CaMKII) [8], calcineurin [9] and SynGAP [10], which activate a wide variety of signal transduction pathways in response to synaptic activity. These signals both feed back onto the receptors to control synaptic strength, and transduce signals from the synapse to the interior of the cell to regulate transcription, translation and metabolism [3,11]
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