Module 12: Figure inositol depletion hypothesis

Inositol depletion hypothesis.

A key component of the inositol depletion hypothesis is that manic-depressive illness is caused by a remodelling of the neural signalsome, resulting in excessive signalling by the phosphoinositide signalling pathway. When operating normally (top panel), neurotransmitters induce a small hydrolysis of PtdIns4,5P2 to give normal levels of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The former is then recycled back to inositol, which is used to resynthesize PtdIns (PI). In manic depression, it is argued that a phenotypic modification has resulted in a remodelled neural signalsome, which is set too high and delivers excessive signals (middle panel). This remodelled signalsome is corrected by Li+ or valproate that both act to reduce the supply of the inositol required to resynthesize PI (bottom panel). Through this depletion of inositol, the overactive phosphoinositide signalling pathway returns to its normal operational level.