Ca 2+ /Calmodulin protein kinase IIα (CaMKIIα) has a central role in regulating neuronal excitability. It is well established that CaMKIIα translocates to excitatory synapses following strong glutamatergic stimuli that induce NMDA-receptor (NMDAR)-dependent longterm potentiation in CA1 hippocampal neurons. We now show that CaMKIIα translocates to inhibitory but not excitatory synapses in response to more moderate NMDAR-activating stimuli that trigger GABA A -receptor (GABA A R) insertion and enhance inhibitory transmission. Such moderate NMDAR activation causes Thr286 autophosphorylation of CaMKIIα, which our results demonstrate is necessary and sufficient, under basal conditions, to localize CaMKIIα at inhibitory synapses and enhance surface GABA A R expression. Although stronger glutamatergic stimulation coupled to AMPA receptor insertion also elicits Thr286 autophosphorylation, accumulation of CaMKIIα at inhibitory synapses is prevented under these conditions by the phosphatase calcineurin. This preferential targeting of CaMKIIα to glutamatergic or GABAergic synapses provides neurons with a mechanism whereby activity can selectively potentiate excitation or inhibition through a single kinase mediator.C a 2+ /Calmodulin protein kinase IIα (CaMKIIα) is essential for NMDA receptor (NMDAR)-dependent potentiation of many excitatory synapses (1, 2). However, CaMKIIα also directly phosphorylates the inhibitory GABA A receptor (GABA A R) α1, β2, β3, and γ2 subunits (3-5). CaMKIIα activation increases GABA A Rs in synaptosomal preparations (6), and potentiates GABA A R-mediated currents in neurons of the spinal cord dorsal horn (7), cortex (8), cerebellum (9, 10), and hippocampus (7, 11). We recently reported that hippocampal inhibitory synapses are potentiated upon activation of NMDARs through a CaMKIIα-dependent insertion of GABA A Rs into the membrane (12). The similar role of CaMKIIα in NMDAR-dependent excitatory and inhibitory potentiation raises the question of how specificity in the modulation of excitatory or inhibitory synapses is maintained.CaMKIIα translocates to excitatory synapses on dendritic spines following long-term potentiation (LTP) induction (13,14), glutamate receptor activation (15-17), or sensory stimulation in vivo (18). However, it is not known whether CaMKIIα must similarly translocate to inhibitory synapses on dendritic shafts to modulate GABAergic transmission. If so, an understanding of the differential regulation of CaMKIIα targeting to inhibitory and excitatory synapses would provide important insight into the control of neuronal excitability.Here we show that although strong activation of NMDARs induces translocation of CaMKIIα to excitatory synapses and enhances surface AMPAR levels, a weaker activation of NMDARs localizes CaMKIIα to inhibitory synapses. This differential translocation of CaMKIIα is dependent on the activation of calcineurin (CaN), which prevents CaMKIIα targeting to inhibitory synapses in response to strong stimuli. Analysis of CaMKIIα mutants further reveals that whe...

Pompe disease is due to a deficiency in acid-α-glucosidase (GAA) and results in debilitating skeletal muscle wasting, characterized by the accumulation of glycogen and autophagic vesicles. Given the role of lysosomes as a platform for mTORC1 activation, we examined mTORC1 activity in models of Pompe disease. GAA-knockdown C2C12 myoblasts and GAA-deficient human skin fibroblasts of infantile Pompe patients were found to have decreased mTORC1 activation. Treatment with the cell-permeable leucine analog l-leucyl-l-leucine methyl ester restored mTORC1 activation. In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine-treated Pompe mice showed increased spontaneous activity and running capacity, with reduced muscle protein breakdown and glycogen accumulation. Together, these data demonstrate that GAA deficiency results in reduced mTORC1 activation that is partly responsible for the skeletal muscle wasting phenotype. Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model.

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