Jonny Daborg
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disease (Myers et al. 1996). This leaves a lot to explain, and probably several
small effect susceptibility genes work together in a complex manner to cause
the disease. Other risk factors are female sex, and vascular disease and its
associated risk factors (Reitz et al. 2011; Bendlin et al. 2010).
1.2
Synapses
The brain is the organ responsible for our mental experiences and abilities. It
achieves this through the workings of a complex network of neurons and glial
cells. The human brain houses approximately 100 billion neurons, these are
interconnected via approximately 100 trillion synapses (Squire 2008).
1.2.1
Synaptic transmission
Synapses transfer, process and store information; accordingly, the synapse
should be regarded as the ultimate functional unit in the central nervous
system (CNS). The vast majority of synapses in the brain are glutamatergic
(Megias et al. 2001), meaning that the transmitter substance released from the
presynaptic bouton in order to convey a signal from the presynaptic cell to
the postsynaptic cell, is glutamate. There also exist GABAergic synapses,
these are typically inhibitory; further there is a class of modulatory synapses
which utilize a vast range of transmitters, modulating neural activity via
volume transmission, the lack of specificity is why these structures should
not be considered as synapses.
The basis for neural transmission is excitability. When a neuron is excited
enough, it fires an action potential along its axon, thereby increasing the
probability of exciting the neurons it is connected to. Excitability is regulated
in part by the neuron itself, this is called intrinsic excitability, and in part by
the sum of synaptic input it receives from other neurons, extrinsic
excitability. Extrinsic excitability is positively regulated by excitatory
synaptic input, and negatively regulated by inhibitory synaptic input – the
balance between excitation and inhibition is of utmost importance in neuronal
networks.
When a great enough number of excitatory synapses are activated, either
spatially or temporally, onto a given neuron, it will fire an action potential
that will spread along its axon, reaching all of the presynaptic terminals
where it will give rise to a Ca
2+
transient, and through this momentarily
increase the probability of transmitter release, if transmitter is released, the
transmitter substance will diffuse over the synaptic cleft and bind to receptor
molecules in the postsynaptic membrane. These receptors are coupled to ion
Synaptic elimination and the complement system in Alzheimer’s disease
10
channels, and in the case of an excitatory synapse, this opening will lead to a
transient depolarisation of the postsynaptic membrane, known as an
excitatory postsynaptic potential (EPSP). If this EPSP is accompanied by
several other EPSPs in the postsynaptic neuron, this neuron will in turn
convey the signal to the neurons it is connected to. However, this is not a
linear process; it depends on the efficacy of each synapse, if the signal will be
transferred to the postsynaptic neuron.
Synaptic efficacy is determined by three parameters, n*p*q, where n is the
number of synapses or release sites, p is the release probability of a single
synaptic vesicle, and q is the quantal size, which is the magnitude of the
postsynaptic response to release of a single synaptic vesicle (Korn and Faber
1991).
1.2.2
Synaptic plasticity
Plasticity is a fundamental aspect of neural networks - neither intrinsic
excitability nor synaptic efficacy is fixed. These parameters are constantly
changing in an activity-dependent manner. During development these
phenomena ensure that the neuronal network is efficiently wired; in the more
mature brain, however, they provide the brain with the necessary means to
adapt to a changing environment, and to store information, thus enabling
anticipation of the future (Kandel and O'Dell 1992).
One of the more thoroughly investigated forms of plasticity is long-term
potentiation (LTP) of the glutamate synapse in the hippocampus (Kerchner
and Nicoll 2008). LTP is commonly regarded as the neurophysiological
substrate for learning and memory. Although there are good reasons to
believe that this is actually true, it has not been shown that LTP is neither
necessary nor sufficient for learning and memory (Martin et al. 2000). The
concept was invented by Donald Hebb in the monumental book The
organisation of behaviour (Hebb 1949). Briefly, he suggested that the
connections between neurons that are active simultaneously, should be
strengthened, thus providing a physiological substrate for lasting association.
More than two decades later this hypothetical phenomenon was indeed
observed by use of extracellular field recordings in rabbits (Bliss and Lomo
1973), and spurred new interest in the search for the engram. A puzzling
question that was left unanswered was how two neurons could “know” that
they were active simultaneously. The putative coincidence detector was
finally shown to be the N-methyl-D-aspartate receptor (NMDAR) by
Wigström and Gustafsson in 1986 (Wigstrom and Gustafsson 1986). The
NMDAR is both voltage- and ligand-gated, meaning that in order for the