Biology Reference
In-Depth Information
substrates by which synaptic memory mechanisms are disrupted remain poorly
understood. A primary locus of excitatory synaptic transmission in the mammalian
central nervous system is the dendritic spine. These protrusions from dendritic shafts
exhibit dynamic changes in number, size and shape in response to variation in hormonal
status, developmental stage, and changes in afferent input. Not surprisingly, loss of spine
density has been linked to cognitive and memory impairment in AD, but the underlying
mechanism(s) in this case is uncertain, as well. Intriguingly, findings in other
neurodegenerative diseases indicate that a broadly similar process of synaptic dysfunction
is induced by diffusible oligomers of misfolded proteins. This chapter will present a
critical review of current knowledge on the bases of synaptic dysfunction in
neurodegenerative diseases, with a focus on AD, and will encompass both amyloid- and
non-amyloid-driven mechanisms. Where appropriate, consideration will also be given to
emerging data which point to potential therapeutic approaches for ameliorating the
cognitive and memory deficits associated with these disorders.
Keywords:
plasticity, synapse, dendrites, spines, glutamatergic, neurodegeneration, memory,
cognition, Alzheimer's disease, Parkinson's disease
I
NTRODUCTION
Neuroplasticity comprises a spectrum of structural elements: long-term potentiation
(LTP), synaptic efficacy and remodeling, synaptogenesis, neuritogenesis including axonal
sprouting and dendritic remodeling, and neurogenesis. Synaptic strengthening, which requires
activation of pre- and postsynaptic elements underlies the phenomenon of LTP as a model of
memory formation, and which is associated with synapse dynamics including formation and
removal of synapses and changes in synapse morphology [Chang and Greenough, 1984;
Martin
et al.,
2000]. Signals of plasticity include intraneuronal (anterograde and retrograde),
interneuronal (transsynaptic and extra/parasynaptic) as well as intercellular signaling through
glia [Cotman and Nieto-Sampedro 1984]. Those neuronal systems playing a crucial role in
higher brain functions (e.g. learning, memory, cognition) such as hippocampus, neocortical
association areas, and the cholinergic basal forebrain neurons, retain a high degree of
structural plasticity throughout life [Arendt, 2004]. A number of molecules acting as such
signals will be discussed in the course of this article.
The adult central nervous system (CNS) responds to injury with limited yet sometimes
effective restoration of synaptic circuitry. Whether compensatory growth is widespread and
whether it reverses cognitive deficits is a subject still debated [Cotman
et al.,
1991; Masliah
et al.,
1995]. Functional recovery requires that reactive synaptogenesis not exacerbate
circuitry dysfunction [Cotman
et al.,
1991; Masliah et al., 1991]. Brain self-reorganization
continuously balances synapse formation and removal as well as neurite sprouting and
retraction, and in some conditions, inhibition of sprouting may actually be protective by
sequestering dysfunctional neurons [Mesulam, 2000]. At the other end of the spectrum,
mechanisms that regulate neuronal plasticity might be instrumental in neurodegenerative
diseases. Intriguingly, brain regions with the highest degree of structural plasticity are those
that take longest to mature during childhood [Braak and Braak, 1996] and are the same
regions with the highest degree of vulnerability during aging and in Alzheimer's disease (AD)
[Braak and Braak, 1991; Arendt, 2004].
