Activation of postsynaptic alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII) by calcium influx is a prerequisite for the induction of long-term potentiation (LTP) at most excitatory synapses in the hippocampus and cortex. Here we show that postsynaptic LTP is unaffected at parallel fiber-Purkinje cell synapses in the cerebellum of alphaCaMKII(-/-) mice. In contrast, a long-term depression (LTD) protocol resulted in only transient depression in juvenile alphaCaMKII(-/-) mutants and in robust potentiation in adult mutants. This suggests that the function of alphaCaMKII in parallel fiber-Purkinje cell plasticity is opposite to its function at excitatory hippocampal and cortical synapses. Furthermore, alphaCaMKII(-/-) mice showed impaired gain-increase adaptation of both the vestibular ocular reflex and optokinetic reflex. Since Purkinje cells are the only cells in the cerebellum that express alphaCaMKII, our data suggest that an impairment of parallel fiber LTD, while leaving LTP intact, is sufficient to disrupt this form of cerebellar learning.

de Jeu, Marcel and Cyriel Pennartz. Circadian modulation of GABA function in the rat suprachiasmatic nucleus: excitatory effects during the night phase. J Neurophysiol 87: 834 -844, 2002; 10.1152/ jn.00241.2001. Gramicidin-perforated patch-clamp recordings were made from slices of the suprachiasmatic nucleus (SCN) of adult rats to characterize the role of ␥-amino butyric acid (GABA) in the circadian timing system. During the day, activation of GABA A receptors hyperpolarized the membrane of SCN neurons. During the night, however, activation of GABA A receptors either hyperpolarized or depolarized the membrane. These night-restricted depolarizations in a large subset of SCN neurons were capable of triggering spikes and thus appeared to be excitatory. The GABA A reversal potentials of SCN neurons revealed a significant day-night difference with more depolarized GABA A reversal potentials during the night than during the day. The emergence of depolarizing GABA A -mediated responses in a subset of SCN neurons at night can be ascribed to a depolarizing shift in GABA A reversal potential. The GABA A receptor antagonist bicuculline (12.5 M) increased the spontaneous firing rate of all SCN neurons during the day, indicating that spontaneous GABA A -mediated inputs inhibited the SCN neurons during this period. The effect of bicuculline (12.5 M) on the spontaneous firing rate of SCN neurons during the night was heterogeneous due to the mixture of depolarizing and hyperpolarizing GABA A -mediated inputs during this period. We conclude that GABA uniformly acts as an inhibitory transmitter during the day but excites a large subset of SCN neurons at night. This day-night modulation of GABAergic neurotransmission provides the SCN with a time-dependent gating mechanism that may counteract propagation of excitatory signals throughout the biological clock at day but promotes it at night.

The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedback information from the cerebellar nuclei (CN), thereby occupying a central position in the olivo-cerebellar loop. Here, we investigated the feedback input from the CN to the IO in vivo in mice using the whole-cell patch-clamp technique. This approach allows us to study how the CN-feedback input is integrated with the activity of olivary neurons, while the olivo-cerebellar system and its connections are intact. Our results show how IO neurons respond to CN stimulation sequentially with: i) a short depolarization (EPSP), ii) a hyperpolarization (IPSP) and iii) a rebound depolarization. The latter two phenomena can also be evoked without the EPSPs. The IPSP is sensitive to a GABAA receptor blocker. The IPSP suppresses suprathreshold and subthreshold activity and is generated mainly by activation of the GABAA receptors. The rebound depolarization re-initiates and temporarily phase locks the subthreshold oscillations. Lack of electrotonical coupling does not affect the IPSP of individual olivary neurons, nor the sensitivity of its GABAA receptors to blockers. The GABAergic feedback input from the CN does not only temporarily block the transmission of signals through the IO, it also isolates neurons from the network by shunting the junction current and re-initiates the temporal pattern after a fixed time point. These data suggest that the IO not only functions as a cerebellar controlled gating device, but also operates as a pattern generator for controlling motor timing and/or learning.

Eye movements are very important in order to track an object or to stabilize an image on the retina during movement. Animals without a fovea, such as the mouse, have a limited capacity to lock their eyes onto a target. In contrast to these target directed eye movements, compensatory ocular eye movements are easily elicited in afoveate animals 1,2,3,4 . Compensatory ocular movements are generated by processing vestibular and optokinetic information into a command signal that will drive the eye muscles. The processing of the vestibular and optokinetic information can be investigated separately and together, allowing the specification of a deficit in the oculomotor system. The oculomotor system can be tested by evoking an optokinetic reflex (OKR), vestibulo-ocular reflex (VOR) or a visually-enhanced vestibulo-ocular reflex (VVOR). The OKR is a reflex movement that compensates for "full-field" image movements on the retina, whereas the VOR is a reflex eye movement that compensates head movements. The VVOR is a reflex eye movement that uses both vestibular as well as optokinetic information to make the appropriate compensation. The cerebellum monitors and is able to adjust these compensatory eye movements. Therefore, oculography is a very powerful tool to investigate brain-behavior relationship under normal as well as under pathological conditions (f.e. of vestibular, ocular and/or cerebellar origin).Testing the oculomotor system, as a behavioral paradigm, is interesting for several reasons. First, the oculomotor system is a well understood neural system 5 . Second, the oculomotor system is relative simple 6 ; the amount of possible eye movement is limited by its ball-in-socket architecture ("single joint") and the three pairs of extra-ocular muscles 7 . Third, the behavioral output and sensory input can easily be measured, which makes this a highly accessible system for quantitative analysis 8 . Many behavioral tests lack this high level of quantitative power. And finally, both performance as well as plasticity of the oculomotor system can be tested, allowing research on learning and memory processes 9 .Genetically modified mice are nowadays widely available and they form an important source for the exploration of brain functions at various levels 10 . In addition, they can be used as models to mimic human diseases. Applying oculography on normal, pharmacologically-treated or genetically modified mice is a powerful research tool to explore the underlying physiology of motor behaviors under normal and pathological conditions. Here, we describe how to measure video-oculography in mice 8 .