Synaptic plasticity and functional stabilization in the hippocampal formation: possible role in Alzheimer's disease

In this chapter we have explored the hypothesis that reactive synaptogenesis is an adaptive mechanism that can compensate for loss of a fraction of a defined neuronal population. Partial cell loss occurs during the course of aging, neurodegenerative diseases, and minor traumatic brain injuries. As cells are lost or as their function severely declines, new connections made by healthy neurons from within the population can assume parallel functions (homotypic sprouting), or fibers from converging pathways (heterotypic sprouting) can act to boost weakened signals and maintain functional stability. When cell death (or disease) progresses to the point where the pathway is broken, sprouting can no longer maintain information flow along the circuit and thus is unable to preserve function, unless new circuits can also be compensatory as, for example, after unilateral injury. We have analyzed the consequences of cell loss on the nature of circuit regrowth within the primary hippocampal circuits--i.e., the entorhinal-dentate gyrus-CA3-CA1 pathways. Reactive synaptogenesis can occur throughout the system after loss of each major cell population. Homotypic sprouting predominates in several pathways (e.g., dentate gyrus after CA4 loss, CA1 field after CA3 loss), and heterotypic sprouting appears prominent in the dentate gyrus after entorhinal cell loss. Each reactive network as a result of the regrowth can, in principle, still function, if cell loss is partial. The observation that sprouting also occurs in Alzheimer's disease illustrates that a slow and fractional loss of a neuronal assembly can trigger reactive growth in humans even along with a severe neurodegenerative disease. Axon sprouting was predicted in the dentate gyrus after entorhinal cell loss from rodent studies and has now been demonstrated in the brain of Alzheimer's victims. Cholinergic septal inputs, if present, can sprout, thereby enhancing cholinergic function and transmission by entorhinal perforant path fibers. CA4 fibers also sprout, thereby increasing positive feedback on granule neurons. At present, however, the functional significance of these mechanisms has yet to be established in clinical studies. Alzheimer's disease has a prolonged course with progressive symptoms. We would propose that axon sprouting or reactive synapse formation provides additional stability beyond the decline predicted from cell loss alone (Fig. 8). Thus, the clinical threshold where functions disappear is postponed for longer periods of time. Some reports in the literature are consistent with rapid behavioral decline followed by intervening periods of stability.(ABSTRACT TRUNCATED AT 400 WORDS)