Cannabinoids exert their psychomotor actions through the CB 1 cannabinoid receptor in the brain. Genetic deletion of CB 1 in mice causes various symptoms, including changes in locomotor activity, increased ring catalepsy, supraspinal hypoalgesia, and impaired memory extinction. Although the cerebellar cortex contains the highest level of CB 1 , severe cerebellum-related functional deficits have not been reported in CB 1 knock-out mice. To clarify the roles of CB 1 in cerebellar function, we subjected CB 1 knock-out mice to a delay version of classical eyeblink conditioning. This paradigm is a test for cerebellum-dependent discrete motor learning, in which conditioned stimulus (CS) (352 ms tone) and unconditioned stimulus (US) (100 ms periorbital electrical shock) are coterminated. We found that delay eyeblink conditioning performance was severely impaired in CB 1 knock-out mice. In contrast, they exhibited normal performance in a trace version of eyeblink conditioning with 500 ms stimulus-free interval intervened between the CS offset and the US onset. This paradigm is a test for hippocampus-dependent associative learning. Sensitivity of CB 1 knock-out mice to CS or US was normal, suggesting that impaired delay eyeblink conditioning is attributable to defects in association of responses to CS and US. We also found that intraperitoneal injection of the CB 1 antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] to wild-type mice caused severe impairment in acquisition but not extinction of delay eyeblink conditioning. SR141716A treatment had no effect on trace eyeblink conditioning with a 500 or 750 ms trace interval. These results indicate that endogenous cannabinoid signaling through CB 1 is essential for cerebellum-dependent discrete motor learning, especially for its acquisition.

In mice lacking glutamate receptor subunit delta 2 (GluR delta 2(-/-_ mice), cerebellar long-term depression (LTD) at the parallel fibre-Purkinje cell synapses is disrupted. Unlike the cerebellar LTD-deficient mice previously used for eyeblink conditioning, however, the abnormalities of the GluR delta 2(-/-) mice are restricted to the cerebellar cortex. In delay eyeblink conditionings (interstimulus interval of 252 and 852 ms), in which the conditioned stimulus (CS) overlaps temporally with a coterminating unconditioned stimulus (US), GluR delta 2(-/-) mice are severely impaired in learning, strongly supporting the hypothesis that cerebellar cortical LTD is essential for delay conditioning. In the trace paradigm, in which a stimulus-free trace interval of 500 ms intervened between the CS and US, GluR delta 2(-/-) mice learned as successfully as wild-type mice, indicating that cerebellar LTD is not necessary for trace conditioning. Thus, the present study has revealed a cerebellar LTD-independent learning in eyeblink conditioning.

Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.

Functional crosstalk between cell‐surface and intracellular ion channels plays important roles in excitable cells and is structurally supported by junctophilins (JPs) in muscle cells. Here, we report a novel form of channel crosstalk in cerebellar Purkinje cells (PCs). The generation of slow afterhyperpolarization (sAHP) following complex spikes in PCs required ryanodine receptor (RyR)‐mediated Ca2+‐induced Ca2+ release and the subsequent opening of small‐conductance Ca2+‐activated K+ (SK) channels in somatodendritic regions. Despite the normal expression levels of these channels, sAHP was abolished in PCs from mutant mice lacking neural JP subtypes (JP‐DKO), and this defect was restored by exogenously expressing JPs or enhancing SK channel activation. The stimulation paradigm for inducing long‐term depression (LTD) at parallel fiber–PC synapses adversely established long‐term potentiation in the JP‐DKO cerebellum, primarily due to the sAHP deficiency. Furthermore, JP‐DKO mice exhibited impairments of motor coordination and learning, although normal cerebellar histology was retained. Therefore, JPs support the Ca2+‐mediated communication between voltage‐gated Ca2+ channels, RyRs and SK channels, which modulates the excitability of PCs and is fundamental to cerebellar LTD and motor functions.

In metabotropic glutamate receptor-subtype 1 (mGluR1)-null (mGluR1-/-) mice, cerebellar long-term depression (LTD) and several forms of memory are impaired. However, because mGluR1 is expressed in various brain regions in wild-type mice, it has been difficult to identify which type of memory depends on mGluR1 expressed in a given brain region. Furthermore, severe ataxia in mGluR1-/- mice complicated interpretation of the data from non-cerebellum-dependent tasks. We have generated mGluR1-rescue mice, which express mGluR1 only in Purkinje cells (PCs) of their cerebellum, by introducing the mGluR1alpha transgene into mGluR1-/- mice under the control of a PC-specific promoter. The mGluR1-rescue mouse has normal LTD and displays no apparent ataxia. Therefore, this mouse is the first animal model in which effects of mGluR1 deficiency outside PCs can be studied without cerebellar dysfunction. We used three eyeblink conditioning paradigms with different temporal specificities between conditioned stimulus (CS) and unconditioned stimulus (US). Delay conditioning, in which CS and US coterminate, was impaired in mGluR1-/- mice but normal in mGluR1-rescue mice. However, both strains of mice displayed severe impairment in trace conditionings, in which a stimulus-free interval of 250 or 500 ms intervened between CS and US. We also examined social transmission of food-preference and novel-object-recognition memory tests. In these tasks, mGluR1-rescue mice showed normal short-term but impaired long-term memory. We conclude that mGluR1 in PCs is indispensable for normal learning of association of temporally contiguous stimuli in associative conditioning. In contrast, mGluR1 in other cell types is required for associating discontiguous stimuli and long-term memory formation in nonspatial hippocampus-dependent learning.