Biology Reference
In-Depth Information
“coincidence detector”[11, 12, 31]. The required depolarization in many cases appears to be
mediated by the other major ionotropic glutamate receptor (the amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptors), which are often co-localized with NMDA
receptors. NMDA receptors have slower activation kinetics, longer channel open times, and
higher affinities for glutamate compared to AMPA receptors [32]. NMDA-mediated forms of
LTP can be blocked with compounds such as 2-amino-5-phosphonopentanoic acid (APV), (a
competitive antagonist) or MK-801, (a noncompetitive antagonist) [28]. An important
exception to the above scenario is that the mossy fiber projection from the dentate to CA3
exhibits a NMDA-independent form of LTP [33, 34].
LTP induction in hippocampal brain slices
There are several aspects to LTP methodology, which cannot all be covered in this short
chapter, so only some of the important LTP stimulation inducing protocols are discussed [19].
LTP can be induced by a high-frequency protocol, such as a train of 100 Hz (e.g., three
bursts, with a 500 msec interval between bursts, and where each pulse of a burst is a square
wave with 50 to 100 μs duration). Another experimental paradigm used in the hippocampal
CA1 is primed burst (PB) potentiation. In PB, typically five pulses are used where the first
pulse precedes the last 4 pulses (given at 100 Hz) by 170 ms. In addition, a very effective
LTP-inducing protocol is theta-burst stimulation (TBS). In TBS, a single burst consists of 4
pulses at 100 Hz. However, this burst is typically repeated several times where some
protocols consist of a train of 5 bursts each separated by 200 ms. The train can also be
repeated 2 to 6 times with 10 second intervals between each train. An important characteristic
of TBS protocols is the inter-burst interval of 200 msec - a time period during which
inhibitory post-synaptic potentials (IPSPs) are difficult to recruit. The absence of IPSPs in
this interval is due to the fact that the refractory period for IPSPs ranges from 200-500 msec -
a period longer than the inter-burst interval. Without IPSP recruitment, repeated stimulation
allows for more effective temporal summation of excitatory post-synaptic potentials (EPSPs).
One major advantage of theta burst stimulation over standard high frequency protocols is that
theta burst appears to more closely simulate the physiological activation pattern of nerve cells
during theta brain wave activity as observed with EEG. Likewise in PB protocols, which are
also presumably closer to normal patterns of activation, only a small number of pulses are
applied (unlike high frequency protocols).
In vivo LTP
Frequencies for in vivo LTP have ranged from 100-400 Hz; however, several bursts at
400 Hz appears to be very popular [19]. In addition, it seems that early studies (ie., before
1977) reported in vivo LTP using 10-100 Hz (2-20 sec trains), but these stimuli produced
strong frequency potentiation, and in unanesthetized animals generated epileptiform
afterdischarges (AD). ADs can be defined as persistent trains of rhythmic ictal
synchronizations, which take place after an initial spike (i.e., a fast electrographic transient).
In vivo LTP can be accomplished in freely moving or anesthetized animals where the brain is
