Abstract : Synapsin III, the most recently described member of the synapsin gene family, displays a gene structure and protein domain structure similar to those of synapsins I and II. In this report, however, we describe major differences in the temporal‐ and tissue‐specific expressions of synapsin III. Whereas synapsins I and II each give rise to two isoforms that are expressed predominantly in adult brain, there are at least six synapsin III transcripts (synapsin IIIa‐IIIf) that differ with respect to tissue‐ and developmental stage‐specific expression. Three of the neuronal transcripts are detected in fetal and to a lesser extent in adult brain (IIIa‐IIIc), whereas one (IIId) is detected only in fetal brain. Two additional transcripts (IIIe and IIIf) are detected only in nonneuronal tissues. A putative second promoter, which is contained within an intron in the synapsin III gene locus, appears to generate the nonneuronal synapsin IIIe and IIIf transcripts. This level of genome complexity is far greater than that described previously for the synapsin I and II genes and suggests that synapsin III may have functions distinct from those described for synapsins I and II.
Synapsin III is a neuron‐specific phosphoprotein that plays an important role in synaptic transmission and neural development. While synapsin III is abundant in embryonic brain, expression of the protein in adults is reduced and limited primarily to the hippocampus, olfactory bulb and cerebral cortex. Given the specificity of synapsin III to these brain areas and because it plays a role in neurogenesis in the dentate gyrus, we investigated whether it may affect learning and memory processes in mice. To address this point, synapsin III knockout mice were examined in a general behavioral screen, several tests to assess learning and memory function, and conditioned fear. Mutant animals displayed no anomalies in sensory and motor function or in anxiety‐ and depressive‐like behaviors. Although mutants showed minor alterations in the Morris water maze, they were deficient in object recognition 24 h and 10 days after training and in social transmission of food preference at 20 min and 24 h. In addition, mutants displayed abnormal responses in contextual and cued fear conditioning when tested 1 or 24 h after conditioning. The synapsin III knockout mice also showed aberrant responses in fear‐potentiated startle. As synapsin III protein is decreased in schizophrenic brain and because the mutant mice do not harbor obvious anatomical deficits or neurological disorders, these mutants may represent a unique neurodevelopmental model for dissecting the molecular pathways that are related to certain aspects of schizophrenia and related disorders.
The 5-HT2C receptor2 is a prominent serotonin receptor that is uniquely expressed in the central nervous system and has been implicated in a variety of psychiatric diseases. While characterizing the 5-HT2C receptor gene, we observed that the mRNA contains a long 3' untranslated region that binds multiple brain proteins. Two proteins, molecular weights 55 and 58 kDa, were of particular interest because they were detected only in brain regions known to express the 5-HT2C receptor abundantly, namely, the hippocampus and cortex. These proteins bind with high affinity to the 5-HT2C receptor mRNA at its extreme 3' end (Kd = 1.8 nM), and binding can be specifically competed by selected regions of the 3' UTR. Furthermore, binding of the 55 and 58 kDa proteins to the mRNA is directionally specific and shows preference for an AU-rich loop containing 6 to 7 nucleotides. These results suggest the possibility that these two brain specific proteins may play a role in the post-transcriptional regulation of the 5-HT2C receptor, and that post-transcriptional control of 5-HT2C receptor expression may be an important regulatory mechanism which has not been previously reported for this serotonin receptor subtype.
There is increasing evidence implicating proteins associated with the synaptic vesicle, a presynaptic organelle that is essential for neurotransmission and synaptic connectivity, to schizophrenia. This chapter reviews the postmortem, genetic, and behavioral data, examines the trends and their relevance. List of Abbreviations: GABA, gamma aminobutyric acid; MAPK, mitogen-activated protein kinase; .4 Synaptic vesicle associated proteins and schizophrenia SNARE, soluble N-ethylmaleimide-sensitive fusion attachment protein receptor; SNP, single nucleotide polymorphism
Although fucose-alpha(1-2)-galactose [Fucalpha(1-2)Gal] carbohydrates have been implicated in cognitive processes such as long-term memory, the molecular mechanisms by which these sugars influence neuronal communication are not well understood. Here, we present molecular insights into the functions of Fucalpha(1-2)Gal sugars, demonstrating that they play a role in the regulation of synaptic proteins and neuronal morphology. We show that synapsins Ia and Ib, synapse-specific proteins involved in neurotransmitter release and synaptogenesis, are the major Fucalpha(1-2)Gal glycoproteins in mature cultured neurons and the adult rat hippocampus. Fucosylation has profound effects on the expression and turnover of synapsin in cells and protects synapsin from degradation by the calcium-activated protease calpain. Our studies suggest that defucosylation of synapsin has critical consequences for neuronal growth and morphology, leading to stunted neurite outgrowth and delayed synapse formation. We also demonstrate that Fucalpha(1-2)Gal carbohydrates are not limited to synapsin but are found on additional glycoproteins involved in modulating neuronal architecture. Together, our studies identify important roles for Fucalpha(1-2)Gal sugars in the regulation of neuronal proteins and morphological changes that may underlie synaptic plasticity.
