Angelman syndrome (AS) is a severe neurological disorder characterized by mental retardation, motor dysfunction and epilepsy. We show that the molecular and cellular deficits of an AS mouse model can be rescued by introducing an additional mutation at the inhibitory phosphorylation site of alphaCaMKII. Moreover, these double mutants no longer show the behavioral deficits seen in AS mice, suggesting that these deficits are the direct result of increased inhibitory phosphorylation of alphaCaMKII.

G12V), which is abundantly localized in axon terminals, we were able to increase the ERK-dependent phosphorylation of synapsin I. This resulted in several presynaptic changes, including a higher density of docked neurotransmitter vesicles in glutamatergic terminals, an increased frequency of miniature EPSCs, and increased paired-pulse facilitation. In addition, we observed facilitated neurotransmitter release selectively during high-frequency activity with consequent increases in long-term potentiation. Moreover, these mice showed dramatic enhancements in hippocampus-dependent learning. Importantly, deletion of synapsin I, an exclusively presynaptic protein, blocked the enhancements of learning, presynaptic plasticity, and long-term potentiation. Together with previous invertebrate studies, these results demonstrate that presynaptic plasticity represents an important evolutionarily conserved mechanism for modulating learning and memory.

L7-PKCI transgenic mice, having a specific lack of parallel fiber-Purkinje cell LTD, were tested with two different mazes to dissociate the relative importance of declarative and procedural components of spatial navigation. Our data bring evidence for a deficit of L7-PKCI mice in the acquisition of an adapted goal-oriented behavior, i.e. in the procedural component of the task. This finding supports the hypothesis that cerebellar LTD may subserve a general sensory-motor adaptation process shared by motor and spatial learning functions.3 Spatial navigation offers a suitable framework to study the ability of animals to adapt their behavior to a specific context, defined here as the combination of the multimodal information sensed by the animal and its internal state at a specific time.Spatial navigation requires at least two complementary processes: (i) the elaboration of a spatial representation of the environment (declarative component), enabling the animal to encode the spatio-temporal relationships among environmental cues or events; (ii) the acquisition of a motor behavior adapted to the context in which navigation takes place (procedural component), permitting the execution of optimal (direct) trajectories toward rewarding locations 1 . Several types of cerebellar animal models have been tested in spatial navigation tasks 2 (Supplementary Note). The consensus that emerged from these studies points toward a role of the cerebellum in mediating the procedural component of the spatial navigation function. We focused on the cellular mechanisms subserving the contribution of the cerebellum in spatial learning. Our working hypothesis is that cerebellar Long-Term synaptic Depression (LTD), occurring at the parallel fiber-Purkinje cell (PF-PC) synapses and required for the acquisition of classical conditioning tasks 3 , may also be necessary for the acquisition of efficient trajectories toward a spatial goal through a basic and common process of sensory-motor adaptation.We (synaptic transmission and plasticity), known to be essential for navigation tasks, appeared also to be conserved in L7-PKCI mice (Supplementary Fig. 1).In order to dissociate the relative importance of the declarative and procedural components of navigation, we adopted two different behavioral paradigms: the Morris water maze (MWM) and a new task called the Starmaze (Fig. 1). In both cases, the animal has to find a fixed hidden platform from random departure locations, which requires the declarative capability of learning a spatial representation of the environment. Yet, in contrast to the MWM task, the Starmaze allows the animal to 4 only swim within alleys guiding its movements. This helps to execute goal-directed trajectories effectively, and reduces the procedural demand of the task.To compare the navigation performances of L7-PKCI mice (n = 14) and their control littermates (n = 15) when solving the hidden-platform version of the MWM, we first used three standard parameters: (i) The mean escape latency, measuring the time employed by ...

Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) current as the cause for increased inhibition in Nf1 mutants. Mechanistically, we demonstrate that HCN1 is a novel NF1-interacting protein for which loss of NF1 results in a concomitant increase of interneuron excitability. Furthermore, the HCN channel agonist lamotrigine rescued the electrophysiological and cognitive deficits in two independent Nf1 mouse models, thereby establishing the importance of HCN channel dysfunction in NF1. Together, our results provide detailed mechanistic insights into the pathophysiology of NF1-associated cognitive defects, and identify a novel target for clinical drug development.

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Using targeted mouse mutants and pharmacologic inhibition of alphaCaMKII, we demonstrate that the alphaCaMKII protein, but not its activation, autophosphorylation or its ability to phosphorylate synapsin I, is required for normal short-term presynaptic plasticity. Furthermore, alphaCaMKII regulates the number of docked vesicles independent of its ability to be activated. These results indicate that alphaCaMKII has a nonenzymatic role in short-term presynaptic plasticity at hippocampal CA3-CA1 synapses.

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