The formation and maintenance of the PF-PC synapse is modulated by the GluD2 receptor (previously called GluR[delta]2 [38, 39]) that is selectively expressed at this synapse but not at the CF synapse [40, 41] and has a specific site of interaction (the N-terminal domain) with the presynaptic neurexin via the synaptic organizer Cbln1 [42-44].
Mutant mice deficient in the GluD2 receptor [28, 29] exhibit impaired formation and stabilization of PF-PC synapses and abnormalities in CF innervation patterns with multiple CF innervation not only around the PC soma but also in PC distal dendrites where PFs normally form synapses.
In the mature PC, GluD2 receptors are selectively localized in dendritic spines postsynaptic to PFs [41, 68].
Interestingly, GluD2 receptors appear in the newly formed spines innervated by PFs and CFs [97].
Blocking electrical activity in adult cerebellar cortex by infusing TTX or a selective AMPA receptor antagonist induces the loss of a large number of synaptic contacts of CF terminal arbors, the expansion of the PF territory which invade the proximal dendritic domain of PCs, and the appearance of a high number of new spines in PC proximal dendrites [34, 36, 97, 98] that express GluD2 receptors.
In addition to the normal mammalian glutamate dehydrogenase gene, GLUD1, primates have a second glutamate dehydrogenase gene,
GLUD2, that is expressed in astrocytes and may be needed in those cells to preserve alpha-ketoglutarate levels in the presence of high glutamine synthetase activity [95].
(21) Likewise, the genes ASPM and MCPH1 are implicated in the size of the brain, as well as PDYN,
GLUD2, COX8, and CMAH which may change brain regulation, cerebral metabolism, and so forth.
Another interesting molecule involved in LTD is glutamate receptor [delta]2 subunit (GluD2), an ionotropic glutamate receptor-related molecule which is specifically expressed on the postsynaptic membrane at parallel fiber-Purkinje cell synapses.
However, how some critical molecules such as GluD2 are involved in LTD has not been clarified yet.
Earlier studies reported deficits of LTD and motor learning in mGluR1 knockout and GluD2 knockout mice.
(8),(9),(45),(83)-(85) Interestingly, we recently found that GluD2 was involved not only in postsynaptic LTD but also in presynaptic LTP.
The PIPSL gene (also an interesting hybrid gene) was inserted into the DNA of a great ape ancestor, and the
GLUD2 gene in an ape ancestor.