A Structure-Function Mechanism for Schizophrenia

Abstract

The multiple etiologies of schizophrenia prompt us to raise the question: what final common pathway can induce a convincing sense of the reality of the hallucinations in this disease? The observation that artificial stimulation of an intermediate order of neurons of a normal nervous system induces hallucinations indicates that the lateral entry of activity (not resulting from canonical synaptic transmission) at intermediate neuronal orders may provide a mechanism for hallucinations. Meaningful hallucinations can be de-constructed into an organized temporal sequence of internal sensations of associatively learned items that occur in the absence of any external stimuli. We hypothesize that these hallucinations are autonomously generated by the re-activation of pathological non-specific functional LINKs formed between the postsynaptic membranes at certain neuronal orders and are examined as a final common mechanism capable of explaining most of the features of the disease. Reversible and stabilizable hemi-fusion between simultaneously activated adjacent postsynaptic membranes is viewed as one of the normal mechanisms for functional LINK formation and is dependent on lipid membrane composition. Methods of removing the proteins that may traverse the non-specifically hemi-fused membrane segments and attempts to replace the phospholipid side chains to convert the membrane composition to a near-normal state may offer therapeutic opportunities.

A supplementary circuit rule-set for the neuronal wiring

“…Furthermore, if non-specific inter-postsynaptic functional LINKs occur at certain neuronal orders, they are expected to cause cognitive deficits via the formation of non-specific semblions, the activation of a new set of neurons, hallucinations resulting from semblances connecting features of different previously associatively learned items and changes in oscillatory neuronal activities resulting in changes in consciousness. Since all these features are seen in schizophrenia, we examined this disease in detail (Vadakkan, 2012b). Since a large number of previous studies show lipid membrane composition changes in schizophrenia, many of which were explained by chromosomal deletions involving proteins in lipid metabolic pathways, possible changes at the postsynaptic lipid membranes were examined.…”

“…Membrane hemi-fusion that can be temporarily and permanently stabilized through the insertion of trans-membrane proteins (Figure 3) can function as re-activatible gates, meeting the requirements of the functional LINKs. The progression of the prodromal state to the disease state where it becomes non-reversible with EFA supplementation can be explained by the insertion of trans-membrane proteins across the hemi-fused inter-postsynaptic membrane segments (Figure 3) (Vadakkan, 2012b). EPSP can spread through the hemi-fused inter-postsynaptic membrane segment to the functionally LINKed postsynaptic membrane (Figure 4) both to induce semblance formation as a system property and to simultaneously allow this EPSP to spread to its neuronal soma (Note: hereafter, inter-postsynaptic functional LINKs and hemi-fused postsynaptic membranes are used interchangeably).…”

“…(D ) Repeated formation of the same hemi-fused inter-postsynaptic membrane segment will lead to its stabilization as a homeostatic cellular process. A trans-membrane protein makes the hemi-fused area temporarily stable, depending on the life-span of the protein or its ability to shift away from the hemi-fused area by lateral displacement [Modified from Vadakkan (2012b)].…”

Disintegration of the Astroglial Domain Organization May Underlie the Loss of Reality Comprehension in Schizophrenia: A Hypothetical Model

“…Most studies have directed their investigations on the mechanism of schizophrenia towards neuronal dysfunctions and impairments and have defined schizophrenia as a "neuro-centric" disorder [9]. However, along with the development of genetics and systematic biology approaches in recent years, the key role of glial cells in the etiopathophysiology of schizophrenia has been demonstrated [10] [11] [12].…”

Pathophysiology of Schizophrenia Based on Impaired Glial-Neuronal Interactions

“…The underlying disconnection hypothesis states that schizophrenia can be understood both in cognitive and pathophysiological terms as a failure of proper functional integration within the brain [4]. Accordingly, schizophrenia may be best understood in terms of abnormal interactions between different brain regions [5,6].…”