Long-term potentiation of the responses to parallel fiber stimulation in mouse cerebellar cortex in vivo

Long-term potentiation (LTP) of parallel fiber-Purkinje cell (PF-PC) synapses in the cerebellum has been suggested to underlie aspects of motor learning. Previous in vitro studies have primarily used low frequency PF stimulation conditioning paradigms to generate either presynaptic PF-PC LTP (4-8 Hz) or postsynaptic PF-PC LTP (1 Hz). Little is known about the conditions that evoke PF-PC LTP in vivo. High frequency stimulation in vivo increases PC responsiveness to peripheral stimuli; however, neither the site of action nor the signaling pathways involved have been examined. Using flavoprotein autofluorescence optical imaging in the FVB mouse in vivo, this report describes that a conditioning stimulation consisting of a high frequency burst of PF stimulation (100 Hz, 15 pulse trains every 3 s for 5 min) evokes a long-term increase in the response to PF stimulation. Following the conditioning stimulation, the response to PF stimulation increases over 20 min to ∼130% above baseline and this potentiation persists for at least 2 h. Field potential recordings of the responses to PF stimulation show that the postsynaptic component is potentiated but the presynaptic, parallel fiber volley is not. Paired-pulse facilitation does not change after the conditioning stimulation, suggesting the potentiation occurs postsynaptically. Blocking non-NMDA (N-methyl-d-aspartic acid) ionotropic glutamate receptors with DNQX (6,7-dinitroquinoxaline-2,3-dione disodium salt, 50 μM, bath application) during the conditioning stimulation has no effect on the long-term increase in fluorescence. However, blocking subtype I metabotropic glutamate receptors (mGLuR₁) with LY367385 (200 μM) during the conditioning stimulation abolishes the long-term increase in fluorescence. Blocking GABAergic neurotransmission is not required to evoke this long-term potentiation. Blocking GABA_A receptors reduces but does not eliminate the long-term potentiation. Therefore, this study demonstrates that high frequency PF stimulation generates long-term potentiation of PF-PC synapses in vivo. This novel form of LTP is generated primarily postsynaptically and is mediated by mGluR₁ receptors.