Possible mechanism of schizophrenia origin by excess GABA and synaptic pruning

Abstract

Schizophrenia is a psychotic disorder that affects approximately 1% of the global population. However, the etiology of this illness remains a subject of debate. One of the proposed mechanisms underlying schizophrenia is the synaptic pruning mediated by microglia in the brains of individuals with schizophrenia, although the precise mechanisms of this process remain elusive. In this regard, we propose that the potential development of the disease stems from both a genetic predisposition leading to an excessive production of GABAergic neurons and an exaggerated effort to maintain the E/I (excitation/inhibition) balance in the brain.

Keywords: GABA synaptic pruning; Schizophrenia.

Fig. 1

The pruning process (schematic). E and I powers are depicted during its development. Normal powers are shown in the first frame while increased GABAergic power (by a factor C, here taken as 50%) controlled by the genetic code in schizophrenia patients is shown in the second frame. The two initial pruning stages (overexpressed by a factor b here taken as 0.5) are shown in the next two frames. This process continues until the final power balance depicted in the last frame (the possible situation in schizophrenia patients) is approximately reached. Note that the values of C and b used here are only for demonstration purposes. Actual values are possibly smaller. Note also that the E/I ratio in both the normal and the final stages is 4:1.

Fig. 2

Compared to Fig. 1 final result, both E and I powers are reduced by a fraction $D=C\frac{b}{1-b}$. It depicts this final power reduction fraction of neurons of both modes as a function of the fraction of microglial "over-functioning", for several values of C – the initial genetically encoded excess percentage of GABAergic neurons. Inset: enlarged picture of the cases of small b values.