Postsynaptic density (PSD)-95, the most abundant postsynaptic scaffolding protein, plays a pivotal role in synapse development and function. Continuous palmitoylation cycles on PSD-95 are essential for its synaptic clustering and regulation of AMPA receptor function. However, molecular mechanisms for palmitate cycling on PSD-95 remain incompletely understood, as PSD-95 depalmitoylating enzymes remain unknown. Here, we isolated 38 mouse or rat serine hydrolases and found that a subset specifically depalmitoylated PSD-95 in heterologous cells. These enzymes showed distinct substrate specificity. ␣/␤-Hydrolase domain-containing protein 17 members (ABHD17A, 17B, and 17C), showing the strongest depalmitoylating activity to PSD-95, showed different localization from other candidates in rat hippocampal neurons, and were distributed to recycling endosomes, the dendritic plasma membrane, and the synaptic fraction. Expression of ABHD17 in neurons selectively reduced PSD-95 palmitoylation and synaptic clustering of PSD-95 and AMPA receptors. Furthermore, taking advantage of the acyl-PEGyl exchange gel shift (APEGS) method, we quantitatively monitored the palmitoylation stoichiometry and the depalmitoylation kinetics of representative synaptic proteins, PSD-95, GluA1, GluN2A, mGluR5, G␣ q , and HRas. Unexpectedly, palmitate on all of them did not turn over in neurons. Uniquely, most of the PSD-95 population underwent rapid palmitoylation cycles, and palmitate cycling on PSD-95 decelerated accompanied by its increased stoichiometry as synapses developed, probably contributing to postsynaptic receptor consolidation. Finally, inhibition of ABHD17 expression dramatically delayed the kinetics of PSD-95 depalmitoylation. This study suggests that local palmitoylation machinery composed of synaptic DHHC palmitoylating enzymes and ABHD17 finely controls the amount of synaptic PSD-95 and synaptic function.

During brain development, Reelin exerts a variety of effects in a context-dependent manner, whereas its underlying molecular mechanisms remain poorly understood. We previously showed that the C-terminal region (CTR) of Reelin is required for efficient induction of phosphorylation of Dab1, an essential adaptor protein for canonical Reelin signaling. However, the physiological significance of the Reelin CTR in vivo remains unexplored. To dissect out Reelin functions, we made a knock-in (KI) mouse in which the Reelin CTR is deleted. The amount of Dab1, an indication of canonical Reelin signaling strength, is increased in the KI mouse, indicating that the CTR is necessary for efficient induction of Dab1 phosphorylation in vivo. Formation of layer structures during embryonic development is normal in the KI mouse. Intriguingly, the marginal zone (MZ) of the cerebral cortex becomes narrower at postnatal stages because upper-layer neurons invade the MZ and their apical dendrites are misoriented and poorly branched. Furthermore, Reelin undergoes proteolytic cleavage by proprotein convertases at a site located 6 residues from the C terminus, and it was suggested that this cleavage abrogates the Reelin binding to the neuronal cell membrane. Results from ectopic expression of mutant Reelin proteins in utero suggest that the dendrite development and maintenance of the MZ require Reelin protein with an intact CTR. These results provide a novel model regarding Reelin functions involving its CTR, which is not required for neuronal migration during embryonic stages but is required for the development and maintenance of the MZ in the postnatal cerebral cortex.

Taurine, a substrate of taurine transporter, has functions as a neuromodulator and antioxidant and beta-alanine, a taurine transporter inhibitor, has a role as a neurotransmitter in the brain, and they were expected to be involved in depression-like behavior and antidepressant treatment. These facts aroused our interest in new capabilities of taurine and beta-alanine. Thus, to investigate the effects of chronic ingestion of taurine- (22.5 mmol/kg diet) supplemented diet and beta-alanine- (22.5 mmol/kg diet) supplemented diet under acute stressful conditions, behavioral changes and brain metabolites were compared with mice fed a control diet. In the open field test, no significant difference was observed in locomotor activity among groups. In the elevated plus-maze test, however, significant increases in the percentage of time spent and entries in the open arms were observed in the beta-alanine-supplemented diet fed group compared to both controls and animals fed with taurine-supplemented diet. Moreover, a significant decrease in the duration of immobility was observed in the taurine-supplemented diet group in the forced swimming test compared to both controls and animals fed with beta-alanine-supplemented diet. Taurine-supplemented diet increased taurine and L: -arginine concentrations in the hypothalamus. In contrast, beta-alanine-supplemented diet decreased the concentration of 5-hydroxyindoleacetic acid, a major metabolite of serotonin, in the hypothalamus. Beta-alanine-supplemented diet also increased carnosine (beta-alanyl-L: -histidine) concentration in the cerebral cortex and hypothalamus, and brain-derived neurotrophic factor concentration in the hippocampus. These results suggested that taurine-supplemented diet had an antidepressant-like effect and beta-alanine-supplemented diet had an anxiolytic-like effect.

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