Functional Imaging of Dendritic Spines In Vivo as Markers of Early Brain Disease Existence

Lay Summary

Determining how and when brain cells fail to communicate in an Alzheimer’s disease model

Using cellular imaging in the mouse model of Alzheimer’s disease and in normal mice,  investigators ultimately plan to determine how synapses (the junction between two brain cells) are normally activated, and the number of synapses that must be lost before initial Alzheimer’s signs and symptoms are triggered. The investigators will receive partial funding first to determine the feasibility of their approach and, if feasible, then receive the remaining funding address these questions.

The human cerebral cortex has approximately 60 trillion synapses. A single nerve cell in the cortex has from 5,000-8,000 synapses- junctions where electrochemical messages are passed from one cell to another.  The process works this way: the cell body sends an electrochemical message (neurotransmitter) down its axon. When the message reaches the axon’s ending, it is released into the synapse. The electrochemical signal is then picked up at the synapse by the neighboring cell’s “dendritic spines,” protrusions like tree branches. The dendritic spines all connect to the dendrite (tree trunk). The message then gets sent from the dendrite to the cell body, and the process starts anew, as nerve cells connect to one another and eventually form neural circuits.

The investigators hypothesize that neural circuits in the cerebral cortex are built with redundancy, such that a modest loss of synapses per neuron does not lead to functional deficits; but, as a higher percentage of synapses become dysfunctional early in disease, single neurons lose their ability to communicate. They will test this hypothesis using two-photon cellular imaging and laser macro-dissection in normal mice and in a mouse model of Alzheimer’s disease. They will determine: 1) normal synaptic activation patterns for a single neuron when it is stimulated; 2) whether specific signals are received by specific dendritic spines or randomly; 3) how many dendritic branches need to be eliminated before a cell no longer functions properly; and 4) whether these findings differ in a mouse model of Alzheimer’s disease. The results may enable the investigators to identify which synapses are especially vulnerable in Alzheimer’s disease, and how extensively synaptic loss can occur before a single brain cell fails to function.

Significance:  The research eventually could lead to the targeting of molecular and gene therapies that stabilize and rescue groups of vulnerable synapses affected in Alzheimer’s disease patients.