Nonfunctional glial proteins in tripartite synapses: a pathophysiological model of schizophrenia

A model for the pathophysiology of schizophrenia is proposed that focuses on an unbalance of transmission in tripartite synapses. Synaptically associated astrocytes should be viewed as integral modulatory elements of tripartite synapses consisting of the presynapse, the postsynapse, and the glial element. Astrocytes may secrete glial binding protein into the synaptic cleft, thus binding free neurotransmitters and thereby reducing the levels of neurotransmitters available for stimulating the postsynapse. Astrocytes also have membrane-bound receptors for neurotransmitters, and when these bind neurotransmitters, the astrocytes upregulate the amount of binding protein secreted into the synapse, resulting in a negative feedback to the presynaptic terminal. The hypothesis presented here is that glia lose their negative feedback function due to loss of function mutations in the genes encoding the binding proteins and glial receptors. The mutations generate proteins that cannot be occupied by their cognate substances of the neuronal system, primarily neurotransmitters. Therefore, the glial-neuronal interaction in tripartite synapses affected becomes totally unbalanced, and the glia lose their inhibitory or boundary-setting function. As a result, neural flux is unconstrained by normal glial boundaries, also the flux of thought on the phenomenological level. Schizophrenia may be caused by the inability to delimit conceptual boundaries.