Most neurons in layer VI of the visual cortex project to the dorsal lateral geniculate nucleus (dLGN). These corticogeniculate projection neurons (CG cells) receive top-down synaptic inputs from upper layers (ULs) and bottom-up inputs from the underlying white matter (WM). Use-dependent plasticity of these synapses in layer VI of the cortex has received less attention than in other layers. In the present study, we used a retrograde tracer injected into dLGN to identify CG cells, and, by analyzing EPSPs evoked by electrical stimulation of the UL or WM site, examined whether these synapses show long-term synaptic plasticity. Theta-burst stimulation induced long-term potentiation (LTP) of activated synapses (hom-LTP) and long-term depression (LTD) of nonactivated synapses (het-LTD) in either pathway. The paired-pulse stimulation protocol and the analysis of coefficient variation of EPSPs suggested postsynaptic induction of these changes except UL-induced het-LTD, which may be presynaptic in origin. Intracellular injection of a Ca(2+)-chelator suggested an involvement of postsynaptic Ca(2+) rise in all types of long-term plasticity. Pharmacological analysis indicated that NMDA receptors and type-5 metabotropic glutamate receptors are involved in WM-induced and UL-induced plasticity, respectively. Analysis with inhibitors and/or in transgenic mice suggested an involvement of cannabinoid type 1 receptors and calcineurin in UL-induced and WM-induced het-LTD, respectively. These results suggest that hom-LTP and het-LTD may play a role in switching the top-down or bottom-up regulation of CG cell function and/or in maintaining stability of synaptic transmission efficacy through different molecular mechanisms.