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in the number [20,21]. This is a current prevailing scheme of the molecular induction
mechanism of cerebellar LTD [22].
One important feature of LTD induction is its requirement for concurrent synaptic inputs
from two pathways, parallel fibers and a climbing fiber. A protocol for LTD induction is
pairing stimulation of parallel fibers and a climbing fiber at 1-4 Hz for 100-600 times. LTD is
induced when each climbing fiber stimulation follows each parallel fiber stimulation with a
delay of up to 250 ms [23,24]. This LTD induction condition is consistent with the Albus
model, which suggests that an error signal coded as a climbing fiber input is fed back to a
Purkinje cell, and depresses the parallel fiber - Purkinje cell synaptic transmission which has
contributed to an inappropriate output.
There are four candidate molecules or ions playing a key role in the coincidence detection
of two inputs. They are Ca 2+ , voltage-gated Ca 2+ channel, IP 3 receptor and PKC (Figure 2).
Ca 2+ enters the cytoplasm through two types of channels, voltage-gated Ca 2+ channel on the
plasma membrane and IP 3 receptor on the endoplasmic reticulum. Cytoplasmic Ca 2+
concentration might reach the threshold for LTD induction only when the two types of
channel open concurrently. The second candidate is voltage-gated Ca 2+ channel. Paired
activation of parallel fibers and a climbing fiber may cause local depolarization larger than
that caused by each. The steep voltage-dependence of open probability of voltage-gated Ca 2+
channel may contribute to the supralinear activation of Ca 2+ channel near the parallel fiber -
Purkinje cell synapses [24]. The third candidate is IP 3 receptor. IP 3 receptor is a type of Ca 2+
channel localized not on the plasma membrane but on the membrane of endoplasmic
reticulum, that is opened by binding to IP 3 . It is known that their opening probability
increases when the cytoplasmic Ca 2+ concentration is increased [25]. Thus, coincident
activation of parallel fibers and a climbing fiber induces a large increase in the intracellular
Ca 2+ concentration depending on the Ca 2+ release from the endoplasmic reticulum [24]. This
response exceeds the simple sum of each response. Computational simulation study supports
a role of IP 3 receptor for the coincidence detection [26]. LTD is absent in a mutant mouse
lacking endoplasmic reticulum in the postsynaptic spines of a PN, which might also support
the role of IP 3 receptor [27]. The fourth candidate is PKCα. PKCα translocates from the
cytoplasm to the plasma membrane by binding Ca 2+ , and then becomes fully activated by
binding DAG [16]. A climbing fiber input induces a large increase in the intracellular Ca 2+
concentration, and parallel fiber inputs increase DAG in the plasma membrane [15]. In the
hippocampus, concurrent activation of Ca 2+ permeable NMDA receptors and mGluR induces
synergistic activation of PKCγ [28]. This result suggests that PKCα integrates the Ca 2+ signal
and the mGluR signal, and may work as a coincidence detector for the LTD induction in a
Purkinje cell. However, a live-imaging study of PKCα tagged with green fluorecent protein
(GFP) reported that the activity of PKCα is not apparently prolonged by the coincident
activation of Ca 2+ channel and mGluR1 [29]. Considering the requirement for sequential
inputs from parallel fibers and a climbing fiber in the LTD induction, IP 3 receptor may play a
main role in the coincidence detection [26].
There are other molecules involved in the LTD induction such as mitogen-activated
protein kinase (MAPK), phospholipase A 2 (PLA 2 ), nitric oxide (NO), protein kinase G
(PKG), Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), protein phosphatase 2B
(PP2B, calcineurin), PTPMEG, protein tyrosine kinases and GluRδ2 subunit [30-42]. NO is
released from stellate cells activated by parallel fibers [43-45]. It diffuses into Purkinje cells
and activates guanylyl cyclase, producing cyclic GMP (cGMP) [34,35,46,47]. cGMP
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