Presenilins in synaptic function and disease

Abstract

The presenilin genes harbor approximately 90% of mutations linked to early-onset familial Alzheimer's disease (FAD), but how these mutations cause the disease is still being debated. Genetic analysis in Drosophila and mice demonstrate that presenilin plays essential roles in synaptic function, learning and memory, as well as neuronal survival in the adult brain, and the FAD-linked mutations alter the normal function of presenilin in these processes. Presenilin has also been reported to regulate the calcium homeostasis of intracellular stores, and presynaptic presenilin controls neurotransmitter release and long-term potentiation through modulation of calcium release from intracellular stores. In this review, we highlight recent advances in deciphering the role of presenilin in synaptic function, calcium regulation and disease, and pose key questions for future studies.

Figure 1. The hippocampal network

The hippocampus forms a unidirectional network with input arising from the entorhinal cortex that forms synaptic connections with the dentate gyrus (DG) via the perforant path (PP). Axons from DG project to CA3 pyramidal neurons via the mossy fibres pathway (MF). Axons from CA3 project to CA1 pyramidal neurons via the Schaeffer collateral pathway (SC). These CA1 neurons in turn send the main output back to the entorhinal cortex. CA3 and CA1 neurons can also receive input directly from the perforant path.

Figure 2. Age-dependent neurodegeneration in the forebrain of presenilin conditional double knockout mice (FB-PS cDKO)

Comparison of nissl-stained coronal brain sections of age-matched control (left) and FB-PS cDKO (right) from 2 to 22 months of age. The nissl-stain dyes for cell bodies and is useful to examine cell sizes, numbers and overall morphology of the brain. No detectable differences were found at 2 months of age; however, there was a gradual decrease in cortical thickness with subsequent ages in FB-PS cDKO brains. Black bars delineate the cerebral cortex. Scale bar: 1 mm. (Adapted from Wines-Samuelson et al. [33])

Figure 3. Models depicting how presenilins regulate synaptic function

Upon depolarization, intracellular calcium levels are elevated due to calcium influx through voltage-gated calcium channels (VGCC), store-operated calcium channels (SOC), and calcium induced calcium release (CICR) from intracellular endoplasmic reticulum (ER) stores that is mediated through the ryanodine (RyR) and the inositol-1,4,5-triphosphate receptors (IP₃R). Cytosolic calcium into the ER lumen is mediated through sarco-ER calcium ATPases (SERCAs) pumps. Inactivation of presynaptic presenilins in FB-PS cDKO and CA3-PS cDKO mice alters presynaptic release machinery through its control of calcium release from RyR in the ER thus reducing CICR. The reduction in calcium impairs the probability of neurotransmitter release (Pr), pair-pulse facilitation (PPF) and frequency facilitation (FF) which causes postsynaptic LTP impairments. In addition, inactivation of presynaptic and postsynaptic presenilins in FB-PS cDKO mice decreases NMDAR functions thus contributing to LTP deficits. Meanwhile, inactivation of postsynaptic presenilins in CA1-PS cDKO mice did not display any changes in short- and long-term plasticity.