Optical imaging of long-term depression in the mouse cerebellar cortex in vivo.

Conjunctive stimulation of climbing fiber and parallel fiber inputs results in long-term depression (LTD) at parallel fiber-Purkinje cell synapses. Although hypothesized to play a major role in cerebellar motor learning, there has been no characterization of the cellular and molecular mechanisms of LTD in the whole animal, let alone its spatial properties, both of which are critical to understanding the role of LTD in cerebellar function. Neutral red optical imaging of the cerebellar cortex in the anesthetized mouse was used to visualize the spatial patterns of activation. Stimulation of the parallel fibers evoked a transverse beam of optical activity, and stimulation of the contralateral inferior olive evoked parasagittal bands. Conjunctive stimulation of parallel fibers and climbing fibers induced a long-term decrease (at least 1 hr) in the optical response to subsequent parallel fiber activation confined to the region of interaction between these two inputs. Activation of climbing fibers alone failed to induce the long-term decrease. Field potential recordings confirmed that the depression is postsynaptic and restricted to the interaction site. The long-term depression in the beam was prevented by a group 1 metabotropic glutamate receptor (mGluR(1)) antagonist and was absent in transgenic mice selectively expressing an inhibitor of protein kinase C (PKC) in Purkinje cells. Conversely, the long-term depression occurred in the mGluR(4) knock-out mouse, consistent with its postsynaptic origin. In addition to providing the first visualization of parallel fiber-Purkinje cell LTD in the cerebellar cortex, this study demonstrates the spatial specificity of LTD and its dependence on mGluR(1) and PKC in vivo.