1Biol. Psychiatry 2011 Jan 69: 71-9
TitleLack of change in markers of presynaptic terminal abundance alongside subtle reductions in markers of presynaptic terminal plasticity in prefrontal cortex of schizophrenia patients.
AbstractReduced synaptic connectivity in frontal cortex may contribute to schizophrenia symptoms. While altered messenger RNA (mRNA) and protein expression of various synaptic genes have been found, discrepancies between studies mean a generalizable synaptic pathology has not been identified.
We determined if mRNAs encoding presynaptic proteins enriched in inhibitory (vesicular gamma-aminobutyric acid transporter [VGAT] and complexin 1) and/or excitatory (vesicular glutamate transporter 1 [VGluT1] and complexin 2) terminals are altered in the dorsolateral prefrontal cortex of subjects with schizophrenia (n = 37 patients, n = 37 control subjects). We also measured mRNA expression of markers associated with synaptic plasticity/neurite outgrowth (growth associated protein 43 [GAP43] and neuronal navigators [NAVs] 1 and 2) and mRNAs of other synaptic-associated proteins previously implicated in schizophrenia: dysbindin and vesicle-associated membrane protein 1 (VAMP1) mRNAs using quantitative polymerase chain reaction.
No significant changes in complexin 1, VGAT, complexin 2, VGluT1, dysbindin, NAV2, or VAMP1 mRNA expression were found; however, expression of mRNAs associated with plasticity/cytoskeletal modification (GAP43 and NAV1) was reduced in schizophrenia. Although dysbindin mRNA did not differ in schizophrenia compared with control subjects, dysbindin mRNA positively correlated with GAP43 and NAV1 in schizophrenia but not in control subjects, suggesting low levels of dysbindin may be linked to reduced plasticity in the disease state. No relationships between three dysbindin genetic polymorphisms previously associated with dysbindin mRNA levels were found.
A reduction in the plasticity of synaptic terminals supports the hypothesis that their reduced modifiability may contribute to neuropathology and working memory deficits in schizophrenia.
SCZ Keywordsschizophrenia
2Int. J. Dev. Neurosci. 2011 May 29: 225-36
TitleMolecular evidence that cortical synaptic growth predominates during the first decade of life in humans.
AbstractTheories concerning the pathology of human neurodevelopmental disorders that emerge in adolescence, such as schizophrenia, often hypothesize that there may be a failure of normal cortical synaptic loss or pruning. However, direct evidence that synaptic regression is a major developmental event in the adolescent human cortex is limited. Furthermore, developmental work in rodents suggested that synaptic regression in adolescence is not a major feature of cortical development. Thus, we set out to determine when and to what extent molecular markers of synaptic terminals [synaptophysin (SYP), SNAP-25, syntaxin1A (STX1A), and vesicle-associated membrane protein 1 (VAMP1)] are reduced during postnatal human life spanning from 1 month to 45 years (n = 69) using several different quantitative methods, microarray, qPCR and immunoblotting. We found little evidence for a consistent decrease in synaptic-related molecular markers at any time point, but instead found clear patterns of gradual increases in expression of some presynaptic markers with postnatal age (including SNAP-25, VAMP1 and complexin 1 (CPLX1) mRNAs and 6/6 presynaptic proteins evaluated). A measure of synaptic plasticity [growth-associated protein of 43 kDa (GAP-43)] was elevated in neonates, and continued robust expression throughout life. Since CPLX1 protein is enriched in inhibitory terminals we also tested if the protein product of complexin 2 (CPLX2), which is enriched in excitatory neurons, is more specifically reduced in development. In contrast to CPLX1, which showed a steady increase in both mRNA and protein levels during postnatal development (both r > 0.58, p < 0.001), CPLX2 mRNA decreased from infants to toddlers (r = -0.56, p < 0.001), while CPLX2 protein showed a steady increase until young adulthood (r = 0.55, p < 0.001). Furthermore, we found that indices of the dendrites [microtubule associated protein 2 (MAP2)] and spines (spinophilin and postsynaptic density protein of 95 kDa (PSD95)] showed some evidence of reduction over time at the mRNA level but the opposite pattern, of a developmental increase, was found for PSD95 and spinophilin protein levels. Taken together, the postnatal changes in molecular components of synapses supports the notion that growth and strengthening of synaptic elements is a major developmental event occurring in the frontal cortex throughout childhood and that maintenance of steady state levels of synapse-associated molecules may predominate during human adolescence.
SCZ Keywordsschizophrenia
3J Neural Transm (Vienna) 2016 Feb -1: -1
TitleSNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond.
AbstractMultiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes.
SCZ Keywordsschizophrenia