A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behavior and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behavior deficits. We find that in patDp/+ mice delay eyeblink conditioning—a form of cerebellum-dependent motor learning—is impaired, and observe deregulation of a putative cellular mechanism for motor learning, long-term depression (LTD) at parallel fiber-Purkinje cell synapses. Moreover, developmental elimination of surplus climbing fibers—a model for activity-dependent synaptic pruning—is impaired. These findings point to deficits in synaptic plasticity and pruning as potential causes for motor problems and abnormal circuit development in autism.

At glutamatergic synapses, both long-term potentiation (LTP) and long-term depression (LTD) can be induced at the same synaptic activation frequency. Instructive signals determine whether LTP or LTD is induced, by modulating local calcium transients. Synapses maintain the ability to potentiate or depress over a wide frequency range, but it remains unknown how calcium-controlled plasticity operates when frequency variations alone cause differences in calcium amplitudes. We addressed this problem at cerebellar parallel fiber-Purkinje cell synapses, which can undergo LTD or LTP in response to 1-Hz and 100-Hz stimulation. We observed that high-frequency activation elicits larger spine calcium transients than low-frequency stimulation under all stimulus conditions, but, regardless of activation frequency, climbing fiber (CF) coactivation provides an instructive signal that further enhances calcium transients and promotes LTD. At both frequencies, buffering calcium prevents LTD induction and LTP results instead, identifying the enhanced calcium signal amplitude as the critical parameter contributed by the instructive CF signal. These observations show that it is not absolute calcium amplitudes that determine whether LTD or LTP is evoked but, instead, the LTD threshold slides, thus preserving the requirement for relatively larger calcium transients for LTD than for LTP induction at any given stimulus frequency. Cerebellar LTD depends on the activation of calcium/ calmodulin-dependent kinase II (CaMKII). Using genetically modified (TT305/6VA and T305D) mice, we identified α-CaMKII inhibition upon autophosphorylation at Thr305/306 as a molecular event underlying the threshold shift. This mechanism enables frequencyindependent plasticity control by the instructive CF signal based on relative, not absolute, calcium thresholds.S ynaptic activation frequency is an important factor in the induction of long-term potentiation (LTP) and long-term depression (LTD). For example, it has been shown at Schaffer collateral-CA1 pyramidal cell synapses that application of 900 pulses at 1-3 Hz causes LTD, whereas the same number of pulses applied at 50 Hz causes LTP (1). However, LTP and LTD can also be induced at the same stimulus frequency. This phenomenon has been demonstrated at hippocampal, neocortical, and cerebellar synapses, where potentiation and depression mechanisms operate over a wide range of activation frequencies (2-7). In the neocortex and hippocampus, the level of postsynaptic depolarization determines whether LTP or LTD results from stimulation at a given frequency (2, 5). These voltage-dependent thresholds for LTP and LTD induction reflect thresholds in calcium signal amplitudes (3,4,(8)(9)(10)(11)) that, when maintained for sufficiently long time periods (12), control synaptic plasticity in concert with distinct calcium sensors that are restricted to local microenvironments (13,14).At cerebellar parallel fiber (PF)-Purkinje cell synapses, both LTP and LTD can be induced using 1-Hz and 100-Hz PF stimulation protocols, ...

No abstract

Key points Spike doublets comprise ∼10% of in vivo complex spike events under spontaneous conditions and ∼20% (up to 50%) under evoked conditions. Under near‐physiological slice conditions, single complex spikes do not induce parallel fibre long‐term depression. Doublet stimulation is required to induce long‐term depression with an optimal parallel‐fibre to first‐complex‐spike timing interval of 150 ms. Abstract The classic example of biological supervised learning occurs at cerebellar parallel fibre (PF) to Purkinje cell synapses, comprising the most abundant synapse in the mammalian brain. Long‐term depression (LTD) at these synapses is driven by climbing fibres (CFs), which fire continuously about once per second and therefore generate potential false‐positive events. We show that pairs of complex spikes are required to induce LTD. In vivo, sensory stimuli evoked complex‐spike doublets with intervals ≤150 ms in up to 50% of events. Using realistic [Ca2+]o and [Mg2+]o concentrations in slices, we determined that complex‐spike doublets delivered 100–150 ms after PF stimulus onset were required to trigger PF‐LTD, which is consistent with the requirements for eyeblink conditioning. Inter‐complex spike intervals of 50–150 ms provided optimal decoding. This stimulus pattern prolonged evoked spine calcium signals and promoted CaMKII activation. Doublet activity may provide a means for CF instructive signals to stand out from background firing.

Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites. In the presence of CX546 in the bath, PF-evoked calcium transients were enhanced and prolonged, suggesting that CX546 not only enhances synaptic transmission, but also boosts dendritic calcium signaling at cerebellar synapses. In contrast to previous observations in the hippocampus, however, CX546 applied during cerebellar recordings facilitates long-term depression (LTD) rather than LTP at PF synapses. These findings show that ampakines selectively modify the LTP -LTD balance depending on the brain area and type of synapse, and may provide tools for the targeted regulation of synaptic memories.[Supplemental material is available for this article.]At glutamatergic synapses onto hippocampal and neocortical pyramidal cells, respectively, coincident pre-and postsynaptic activity elicits long-term potentiation (LTP), which typically requires the activation of N-methyl-D-aspartate (NMDA) receptors (Bliss and Collingridge 1993). Long-term depression (LTD), in contrast, may or may not require NMDA receptor activation, but results from activity patterns that activate the postsynaptic neuron in a less efficient or less well-timed manner (Artola and Singer 1993;Kirkwood et al. 1993). It has been suggested that LTP requires a larger calcium signal amplitude for its induction than LTD (Bienenstock et al. 1982;Bear et al. 1987;Hansel et al. 1997). It seems likely that other calcium signaling parameters are crucial as well (Neveu and Zucker 1996;Nevian and Sakmann 2006), but the amplitude of calcium signaling might be the one parameter that most faithfully reflects synaptic input strength during the induction phase. Efforts to develop memory-enhancing drugs have thus focused on the strategy that the magnitude and induction probability of LTP might be enhanced by drugs that boost synaptic transmission and calcium signaling. Ampakines, which are allosteric modulators of AMPA receptors that enhance transmission by slowing both desensitization and deactivation of AMPA receptors (Lynch 2002), have indeed been shown to facilitate LTP induction (Stäubli et al. 1994;Arai et al. 2004). These observations demonstrate that a selective manipulation of synaptic activation strength can affect the LTP induction probability. Moreover, ampakines positively affect memory encoding and recall in humans (Ingvar et al. 1997;Lynch et al. 1997;Lynch and Gall 2006) and reduce effects of sleep deprivation on cognitive performance (Porrino et...