Viral Vectors to Study Synaptic Function - Viral Vector Approaches in Neurobiology and Brain Diseases - page 110

high synaptic activity open NMDAR, leading to calcium entry and
calcium-dependent intracellular signaling. During Hebbian plas-
ticity, a strong calcium increase activates kinases, which drive the
strengthening of synaptic communication by long-term potentia-
tion (LTP) of the AMPAR response, via translocation of AMPAR
to the PSD and spine growth. Alternatively, lower levels of calcium
entry results in the weakening of synapses characterized by long-
term depression (LTD) of the AMPAR response via loss of AMPAR
from the PSD and loss of spines. Hebbian plasticity occurs in a fast
time scale (minutes) and at a few synapses at any one time.
Contrary to Hebbian plasticity, homeostatic synaptic plasticity
occurs slowly over several days and consists mainly in adjusting
overall synaptic input strength to keep neuronal fi ring of the net-
work away from upper and lower limits, within a range useful for
information fl ow [ 2 ]. To equilibrate the hippocampal network,
excitatory neuronal activity is controlled by GABAergic inhibition,
thus creating an excitatory/inhibitory (E/I) balance critical for
normal hippocampal function. It is this E/I balance that is thought
to be maintained by specifi c homeostatic plasticity mechanisms. In
particular, recent evidence points to two types of homeostatic plas-
ticity mechanisms affecting postsynaptic function in the hippocam-
pus: (1) a global network-wide homeostatic plasticity consisting of
scaling up AMPAR function throughout the network upon chronic
decrease of network activity and (2) a cell autonomous downscal-
ing of AMPAR and NMDAR function that affects each neuron
individually when these neurons chronically increase their fi ring
rate [ 2 ]. It is suggested that these homeostatic plasticities are cru-
cial to keep in check the fi ring potential of the CA1 excitatory
neurons and avoid run-away excitation such as in epilepsy [ 2 ].
The different plasticities described above are likely to play
important roles as cellular events that underlie memory formation.
Exactly how they drive memory encoding is still unclear. There is
evidence that specifi c synaptic alterations, mainly of the Hebbian
type described above, occur when rodents are under cognitive
challenge. Indeed, various groups demonstrated that, when
rodents are trained in hippocampus-dependent memory tasks,
spine growth occurs on dendrites of CA1 pyramidal neurons
[ 3 - 6 ], glutamate receptors are phosphorylated and traffi cked to
the PSD [ 7 ], and LTP/LTD-like processes are engaged [ 8 - 13 ].
Within the last 10 years, viral vectors have been extremely use-
ful to investigate the role of specifi c proteins in these types of syn-
aptic plasticities. Several types of viruses have been used to express
proteins of interest such as the sindbis virus, lentivirus, and adeno-
associated virus (AAV) (e.g., [ 14 - 16 ]). Electrophysiological analy-
sis of synaptic function of infected neurons was performed after
either infection of organotypic slices or after in vivo infection (e.g.,
[ 14 , 16 , 17 ]). These studies have helped understanding the role of
proteins of interest in synaptic function in health and in disease
states (e.g., [ 14 , 16 - 19 ]).