[Sensory gating P50 in schizophrenic patients with and without homicide].

OBJECTIVE: To investigate the change of sensory gating P50 in schizophrenic patients with and without homicide. METHODS: The auditory evoked potentials P50 were recorded from 26 schizophrenic patients with homicide (Sch group), 27 schizophrenic patients without homicide (non-Sch group) and 32 normal controls (NC) using conditioning/testing paradigm presented with auditory double click stimuli by EGI 256 dense array. And the same time, their clinical symptoms were evaluated by positive and negative symptom scale (PANSS). RESULTS: (1) Compared with NC, two Sch groups showed no significant difference in amplitude and latency of S1-P50 [amplitude: NC, Sch group, non-Sch group at Fz: (2.4 + or - 1.6) microV, (2.5 + or - 1.5) microV, (3.4 + or - 2.7) microV; latency: NC, Sch group, non-Sch group at Fz: (68 + or - 19) ms, (67 + or - 20) ms, (61 + or - 19) ms; respectively], but a higher amplitude and delayed latency of S2-P50 [amplitude: NC, Sch group, non-Sch group at Fz: (0.8 + or - 0.7) microV, (2.5 + or - 1.6) microV, (3.3 + or - 2.2) microV; latency: NC, Sch group, non-Sch group at Fz: (50 + or - 26) ms, (75 + or - 19) ms and (70 + or - 24) ms respectively] (P < 0.01), and no significant difference in amplitude and latency of S2-P50 between two Sch groups. (2) Compared with NC, two Sch groups showed a higher S2/S1 ratio [NC, Sch group, non-Sch group at Fz: 35 + or - 26, 153 + or - 137, 125 + or - 85, respectively], lower S2-S1 [NC, Sch group, non Sch group at Fz: 1.69 + or - 1.55, 0.08 + or - 2.41 and 0.17 + or - 2.30, respectively] and 100 (1-S2/S1) [NC, Sch group, non-Sch group at Fz: 65 + or - 26, -53 + or - 137 and -25 + or - 85 respectively] (P < 0.01). And there was no significant difference in S2/S1 ratio, S2-S1 and 100 (1-S2/S1) between two Sch groups. (3) Two Sch groups showed no significant difference in PANSS total, P scale, N scale, and G scale [Sch group: (110 + or - 27), (26 + or - 10), (29 + or - 7), (55 + or - 12); non Sch group: (105 + or - 27), (24 + or - 8), (28 + or - 10) and (53 + or - 12) respectively] (P > 0.05), and no significant correlation with S2/S1 ratio, S2-S1 and 100(1-S2/S1) (P > 0.05). CONCLUSION: Sensory gating deficit exists in schizophrenic patients with and without homicide. And it can be quantified by measuring auditory evoked potential P50, but sensory gating P50 has no difference between schizophrenic patients with and without homicide.

The role of Snapin in neurosecretion: snapin knock-out mice exhibit impaired calcium-dependent exocytosis of large dense-core vesicles in chromaffin cells.

Identification of the molecules that regulate the priming of synaptic vesicles for fusion and the structural coupling of the calcium sensor with the soluble N-ethyl maleimide sensitive factor adaptor protein receptor (SNARE)-based fusion machinery is critical for understanding the mechanisms underlying calcium-dependent neurosecretion. Snapin binds to synaptosomal-associated protein 25 kDa (SNAP-25) and enhances the association of the SNARE complex with synaptotagmin. In the present study, we abolished snapin expression in mice and functionally evaluated the role of Snapin in neuroexocytosis. We found that the association of synaptotagmin-1 with SNAP-25 in brain homogenates of snapin mutant mice is impaired. Consequently, the absence of Snapin in embryonic chromaffin cells leads to a significant reduction of calcium-dependent exocytosis resulting from a decreased number of vesicles in releasable pools. Overexpression of Snapin fully rescued this inhibitory effect in the mutant cells. Furthermore, Snapin is relatively enriched in the purified large dense-core vesicles of chromaffin cells and associated with synaptotagmin-1. Thus, our biochemical and electrophysiological studies using snapin knock-out mice demonstrate that Snapin plays a critical role in modulating neurosecretion by stabilizing the release-ready vesicles.

Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons.

Neuron maintenance and survival require late endocytic transport from distal processes to the soma where lysosomes are predominantly localized. Here, we report a role for Snapin in attaching dynein to late endosomes through its intermediate chain (DIC). snapin(-/-) neurons exhibit aberrant accumulation of immature lysosomes, clustering and impaired retrograde transport of late endosomes along processes, reduced lysosomal proteolysis due to impaired delivery of internalized proteins and hydrolase precursors from late endosomes to lysosomes, and impaired clearance of autolysosomes, combined with reduced neuron viability and neurodegeneration. The phenotypes are rescued by expressing the snapin transgene, but not the DIC-binding-defective Snapin-L99K mutant. Snapin overexpression in wild-type neurons enhances late endocytic transport and lysosomal function, whereas expressing the mutant defective in Snapin-DIC coupling shows a dominant-negative effect. Altogether, our study highlights new mechanistic insights into how Snapin-DIC coordinates retrograde transport and late endosomal-lysosomal trafficking critical for autophagy-lysosomal function, and thus neuronal homeostasis.

Snapin facilitates the synchronization of synaptic vesicle fusion.

Synaptic vesicle (SV) fusion is a fine-tuned process requiring a concert of fusion machineries. Using cortical neurons from snapin-deficient mice, we reveal a role for Snapin in facilitating synchronous release. In addition to reduced frequency of miniature excitatory postsynaptic currents (mini-EPSCs) and smaller release-ready vesicle pool (RRP) size, snapin deficiency results in EPSCs with multiple peaks and increased rise and decay times, reflecting "desynchronized" SV fusion. These defects impair both synaptic precision and efficacy during sustained neurotransmission. Transient expression of Snapin not only rescues the slowed kinetics of EPSCs, but also further accelerates the rate found in wild-type neurons. Furthermore, expression of Snapin-C66A, a dimerization-defective mutant with impaired interactions with SNAP-25 and Synaptotagmin, reduces the RRP size but exhibits less effect on synchronized fusion. Our studies provide mechanistic insights into a dual role of Snapin in enhancing the efficacy of SV priming and in fine-tuning synchronous SV fusion.

Snapin associates with late endocytic compartments and interacts with late endosomal SNAREs.

Late endocytic membrane trafficking delivers target materials and newly synthesized hydrolases into lysosomes and is critical for maintaining an efficient degradation process and cellular homoeostasis. Although some features of late endosome-lysosome trafficking have been described, the mechanisms underlying regulation of this event remain to be elucidated. Our previous studies showed that Snapin, as a SNAP25 (25 kDa synaptosome-associated protein)-binding protein, plays a critical role in priming synaptic vesicles for synchronized fusion in neurons. In the present study, we report that Snapin also associates with late endocytic membranous organelles and interacts with the late endosome-targeted SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) complex. Using a genetic mouse model, we further discovered that Snapin is required to maintain a proper balance of the late endocytic protein LAMP-1 (lysosome-associated membrane protein-1) and late endosomal SNARE proteins syntaxin 8 and Vti1b (vesicle transport through interaction with target SNAREs homologue 1b). Deleting the snapin gene in mice selectively led to the accumulation of these proteins in late endocytic organelles. Thus our present study suggests that Snapin serves as an important regulator of the late endocytic fusion machinery, in addition to its established role in regulating synaptic vesicle fusion.

Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation.

Proper distribution of mitochondria within axons and at synapses is critical for neuronal function. While one-third of axonal mitochondria are mobile, a large proportion remains in a stationary phase. However, the mechanisms controlling mitochondrial docking within axons remain elusive. Here, we report a role for axon-targeted syntaphilin (SNPH) in mitochondrial docking through its interaction with microtubules. Axonal mitochondria that contain exogenously or endogenously expressed SNPH lose mobility. Deletion of the mouse snph gene results in a substantially higher proportion of axonal mitochondria in the mobile state and reduces the density of mitochondria in axons. The snph mutant neurons exhibit enhanced short-term facilitation during prolonged stimulation, probably by affecting calcium signaling at presynaptic boutons. This phenotype is fully rescued by reintroducing the snph gene into the mutant neurons. These findings demonstrate a molecular mechanism for controlling mitochondrial docking in axons that has a physiological impact on synaptic function.

Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated protein (DAP) kinase regulates its interaction with Munc18.

Syntaxin-1 is a key component of the synaptic vesicle docking/fusion machinery that binds with VAMP/synaptobrevin and SNAP-25 to form the SNARE complex. Modulation of syntaxin binding properties by protein kinases could be critical to control of neurotransmitter release. Using yeast two-hybrid selection with syntaxin-1A as bait, we have isolated a cDNA encoding the C-terminal domain of death-associated protein (DAP) kinase, a calcium/calmodulin-dependent serine/threonine protein kinase. Expression of DAP kinase in adult rat brain is restricted to particular neuronal subpopulations, including the hippocampus and cerebral cortex. Biochemical studies demonstrate that DAP kinase binds to and phosphorylates syntaxin-1 at serine 188. This phosphorylation event occurs both in vitro and in vivo in a Ca2+-dependent manner. Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking. Our results suggest that syntaxin is a DAP kinase substrate and provide a novel signal transduction pathway by which syntaxin function could be regulated in response to intracellular [Ca2+] and synaptic activity.