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Gerald Thiel - One of the best experts on this subject based on the ideXlab platform.
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Synapsin IIa bundles actin filaments.
Journal of neurochemistry, 2002Co-Authors: Tamie J. Chilcote, Paul Greengard, Eric Schaeffer, Yaw L. Siow, Gerald ThielAbstract:Synapsins are neuron-specific phosphoproteins associated with small synaptic vesicles in the presynaptic nerve terminal. Synapsin I, which has been demonstrated to bundle F-actin in vitro, has been postulated to regulate neurotransmitter release by cross-linking synaptic vesicles to the actin cytoskeleton. To investigate the possible interaction of Synapsin II with actin filaments, we expressed Synapsin II in Spodoptera frugiperda and High Five insect cells using a recombinant baculovirus. Purified recombinant Synapsin IIa was incubated with F-actin, and bundle formation was evaluated by light scattering and electron microscopy. Synapsin IIa was found to bundle actin filaments. Dose-response curves indicated that Synapsin IIa was more potent than Synapsin I in bundling actin filaments. These data suggest that Synapsin IIa may cross-link synaptic vesicles and actin filaments in the nerve terminal.
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The human Synapsin II gene promoter. Possible role for the transcription factor zif268/egr-1, polyoma enhancer activator 3, and AP2.
The Journal of biological chemistry, 1995Co-Authors: Dirk Petersohn, Susanne Schoch, Dirk R. Brinkmann, Gerald ThielAbstract:Abstract Synapsin II is a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. Here we report the cloning and sequencing of the 5′-flanking region of the human Synapsin II gene. This sequence is very GC-rich and lacks a TATA or CAAT box. Two major transcriptional start sites were mapped. A hybrid gene consisting of the Escherichia coli chloramphenicol acetyltransferase gene under the control of 837 base pairs of the Synapsin II 5′-upstream region was transfected into neuronal and non-neuronal cells. While reporter gene expression was low in neuroblastoma and non-neuronal cells, high chloramphenicol acetyltransferase activities were monitored in PC12 pheochromocytoma cells. However, there was no correlation between reporter gene expression in the transfected cells and endogenous Synapsin II immunoreactivity. Using DNA-protein binding assays we showed that the transcription factors zif268/egr-1, polyoma enhancer activator 3 (PEA3), and AP2 specifically contact the Synapsin II promoter DNA in vitro. Moreover, the zif268/egr-1 protein as well as PEA3 were shown to stimulate transcription of a reporter gene containing Synapsin II promoter sequences. In the nervous system, zif268/egr-1 functions as a “third messenger” with a potential role in synaptic plasticity. PEA3 is expressed in the brain and its activity is regulated by proteins encoded from non-nuclear oncogenes. We postulate that zif268/egr-1 and PEA3 couple extracellular signals to long-term responses by regulating Synapsin II gene expression.
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the human Synapsin II gene promoter possible role for the transcription factor zif268 egr 1 polyoma enhancer activator 3 and ap2
Journal of Biological Chemistry, 1995Co-Authors: Dirk Petersohn, Susanne Schoch, Dirk R. Brinkmann, Gerald ThielAbstract:Abstract Synapsin II is a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. Here we report the cloning and sequencing of the 5′-flanking region of the human Synapsin II gene. This sequence is very GC-rich and lacks a TATA or CAAT box. Two major transcriptional start sites were mapped. A hybrid gene consisting of the Escherichia coli chloramphenicol acetyltransferase gene under the control of 837 base pairs of the Synapsin II 5′-upstream region was transfected into neuronal and non-neuronal cells. While reporter gene expression was low in neuroblastoma and non-neuronal cells, high chloramphenicol acetyltransferase activities were monitored in PC12 pheochromocytoma cells. However, there was no correlation between reporter gene expression in the transfected cells and endogenous Synapsin II immunoreactivity. Using DNA-protein binding assays we showed that the transcription factors zif268/egr-1, polyoma enhancer activator 3 (PEA3), and AP2 specifically contact the Synapsin II promoter DNA in vitro. Moreover, the zif268/egr-1 protein as well as PEA3 were shown to stimulate transcription of a reporter gene containing Synapsin II promoter sequences. In the nervous system, zif268/egr-1 functions as a “third messenger” with a potential role in synaptic plasticity. PEA3 is expressed in the brain and its activity is regulated by proteins encoded from non-nuclear oncogenes. We postulate that zif268/egr-1 and PEA3 couple extracellular signals to long-term responses by regulating Synapsin II gene expression.
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Synapsin I, Synapsin II, and Synaptophysin: Marker Proteins of Synaptic Vesicles
Brain pathology (Zurich Switzerland), 1993Co-Authors: Gerald ThielAbstract:The nerve terminal of neurons is filled with small synaptic vesicles, specialized secretory organelles involved in the storage and release of neurotransmitters. The Synapsins are a family of four proteins that are the major peripheral proteins on the cytoplasmic face of synaptic vesicles. Synaptophysin is the major integral membrane protein of synaptic vesicles. The characterization of the Synapsins and of synaptophysin during the last years has revealed exciting information about their structure, regulation and possible function. To understand the role of the Synapsins and synaptophysin in the biology of a nerve cell means to elucidate the fundamental mechanism of brain function, the release of neurotransmitter.
Paul Heggelund - One of the best experts on this subject based on the ideXlab platform.
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Functions of Synapsins in corticothalamic facilitation: important roles of Synapsin I
The Journal of physiology, 2015Co-Authors: Maxim Nikolaev, Paul HeggelundAbstract:Key points The synaptic vesicle associated proteins Synapsin I and Synapsin II have important functions in synaptic short-term plasticity. We investigated their functions in cortical facilitatory feedback to neurons in dorsal lateral geniculate nucleus (dLGN), feedback that has important functions in state-dependent regulation of thalamic transmission of visual input to cortex. We compared results from normal wild-type (WT) mice and Synapsin knockout (KO) mice in several types of synaptic plasticity, and found clear differences between the responses of neurons in the Synapsin I KO and the WT, but no significant differences between the Synapsin II KO and the WT. These results are in contrast to the important role of Synapsin II previously demonstrated in similar types of synaptic plasticity in other brain regions, indicating that the Synapsins can have different roles in similar types of STP in different parts of the brain. Abstract The synaptic vesicle associated proteins Synapsin I (SynI) and Synapsin II (SynII) have important functions in several types of synaptic short-term plasticity in the brain, but their separate functions in different types of synapses are not well known. We investigated possible distinct functions of the two Synapsins in synaptic short-term plasticity at corticothalamic synapses on relay neurons in the dorsal lateral geniculate nucleus. These synapses provide excitatory feedback from visual cortex to the relay cells, feedback that can facilitate transmission of signals from retina to cortex. We compared results from normal wild-type (WT), SynI knockout (KO) and SynII KO mice, in three types of synaptic plasticity mainly linked to presynaptic mechanism. In SynI KO mice, paired-pulse stimulation elicited increased facilitation at short interpulse intervals compared to the WT. Pulse-train stimulation elicited weaker facilitation than in the WT, and also post-tetanic potentiation was weaker in SynI KO than in the WT. Between SynII KO and the WT we found no significant differences. Thus, SynI has important functions in these types of synaptic plasticity at corticothalamic synapses. Interestingly, our data are in contrast to the important role of SynII previously shown for sustained synaptic transmission during intense stimulation in excitatory synapses in other parts of the brain, and our results suggest that SynI and SynII may have different roles in similar types of STP in different parts of the brain.
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Sensitive and critical periods in the development of handling induced seizures in mice lacking Synapsins: Differences between Synapsin I and Synapsin II knockouts
Experimental neurology, 2013Co-Authors: Lars Etholm, Elma Bahonjic, Paul HeggelundAbstract:Abstract Mice lacking either Synapsin I or Synapsin II develop handling induced seizures from around two months of age. In mice lacking Synapsin I (Synapsin 1 knock-out mice, Syn1KO mice) such seizures can either consist of mild myoclonic jerks or of fully developed generalized tonic–clonic seizures, and the two seizure types are quite evenly distributed. In mice lacking Synapsin II (Synapsin 2 knock-out mice, Syn2KO mice) all seizures are in the form of generalized tonic–clonic seizures. Through the use of specialized animal rearing procedures whereby human–animal interaction was minimized (minimal handling procedures), this study investigated effects of handling also prior to the emergence of actual seizures. The effect of minimal handling procedures was significant in both genotypes, but most pronounced in Syn1KO mice. In this genotype, minimal handling reduced the frequency of mild seizures, and completely eliminated generalized tonic–clonic seizures when the animals were tested with regular handling at 4 1/2 months of age. Neither seizure frequency nor generalized tonic–clonic seizures could be re-established through regular handling from 4 1/2 to 8 months. This suggests that the period up to 4 1/2 months constitute a sensitive period for seizures in general, and a critical period for generalized tonic–clonic seizures in this genotype. In Syn2KO mice minimal handling did not remove generalized tonic–clonic seizures, as such seizures were present when handling was introduced at 4 1/2 months. We found an initial reduction of seizure frequency, but the seizure frequency eventually reached levels seen in mice kept under regular handling regimes. Thus, it is unlikely that the period up to 4 1/2 months is a sensitive period in the Syn2KO genotype.
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Neuroethologically delineated differences in the seizure behavior of Synapsin 1 and Synapsin 2 knock-out mice
Epilepsy research, 2012Co-Authors: Lars Etholm, Hung-teh Kao, Elma Bahonjic, S.i. Walaas, Paul HeggelundAbstract:The highly homologous nerve terminal phosphoproteins Synapsin I and Synapsin II have been linked to the pathogenesis of epilepsy through associations between Synapsin gene mutations and epileptic disease in humans and to the observation of handling induced seizures in mice genetically depleted of one or both of these proteins. Whereas seizure behavior in mice lacking both Synapsin I and Synapsin II is well characterized, the seizure behavior in mice lacking either is less well studied. Through so called neuroethologically based analyses of fully established seizure behavior in Synapsin 1 and 2 knock-out mice (Syn1KO and Syn2KO mice) aged 4 1/2 months, this study reveals significant differences in the seizure behavior of the two genotypes: whereas Syn1KO mice show both partial and generalized forebrain seizure activity, Syn2KO mice show only fully generalized forebrain seizures. Analysis of seizure behavior at earlier stages shows that the mature seizure pattern in Syn2KO mice establishes rapidly from the age of ∼2 months, when Syn1KO partial seizures are rare, and Syn1KO generalized seizures are almost absent. The specific behavioral phenotypes of the two strains suggest that the slight differences in structure, function and expression of these highly related proteins could be important factors during seizure generating neural activity.
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Electroencephalographic characterization of seizure activity in the Synapsin I/II double knockout mouse.
Brain research, 2011Co-Authors: Lars Etholm, Henrik Lindén, Torsten Eken, Paul HeggelundAbstract:We present a detailed comparison of the behavioral and electrophysiological development of seizure activity in mice genetically depleted of Synapsin I and Synapsin II (SynDKO mice), based on combined video and surface EEG recordings. SynDKO mice develop handling-induced epileptic seizures at the age of 2 months. The seizures show a very regular behavioral pattern, where activity is initially dominated by truncal muscle contractions followed by various myoclonic elements. Whereas seizure behavior goes through clearly defined transitions, cortical activity as reflected by EEG recordings shows a more gradual development with respect to the emergence of different EEG components and the frequency of these components. No EEG pattern was seen to define a particular seizure behavior. However, myoclonic activity was characterized by more regular patterns of combined sharp waves and spikes. Where countable, the number of myoclonic jerks was significantly correlated to the number of such EEG complexes. Furthermore, some EEG recordings revealed epileptic regular discharges without clear behavioral seizure correlates. Our findings suggest that seizure behavior in SynDKO mice is not solely determined by cortical activity but rather reflects interplay between cortical activity and activity in other brain regions.
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seizure elements and seizure element transitions during tonic clonic seizure activity in the Synapsin i II double knockout mouse a neuroethological description
Epilepsy & Behavior, 2009Co-Authors: Lars Etholm, Paul HeggelundAbstract:Inactivation of genes for the synaptic terminal proteins Synapsin I and Synapsin II leads to development of epileptic seizures in mice (Syn-DKO mice) in which no other behavioral abnormalities or any gross anatomical brain deformities have been reported. In humans, mutated Synapsin I is associated with epilepsy. Thus, the Syn-DKO mouse might model human seizure development. Here we describe a neuroethological analysis of behavioral elements and relationships between these elements during seizures in Syn-DKO mice. The seizure elements belong to one of three clusters each characterized by specific patterns of activity: truncus-dominated elements, myoclonic elements, and running-fit activity. The first two clusters, constituting the majority of seizural activity, evolve quite differently during ongoing seizure activity. Whereas truncus-dominated elements unfold in a strict sequence, the myoclonic elements wax and wane more independently, once myoclonic activity has started. These differences may point to neurobiological mechanisms relevant to both rodent and human epilepsies.
Fabio Benfenati - One of the best experts on this subject based on the ideXlab platform.
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Synapsin I and Synapsin II regulate neurogenesis in the dentate gyrus of adult mice.
Oncotarget, 2018Co-Authors: Raffaella Barbieri, Pietro Baldelli, Fabio Benfenati, Andrea Contestabile, Maria Grazia Ciardo, Nicola Forte, Antonella Marte, Franco OnofriAbstract:Adult neurogenesis is emerging as an important player in brain functions and homeostasis, while impaired or altered adult neurogenesis has been associated with a number of neuropsychiatric diseases, such as depression and epilepsy. Here we investigated the possibility that Synapsins (Syns) I and II, beyond their known functions in developing and mature neurons, also play a role in adult neurogenesis. We performed a systematic evaluation of the distinct stages of neurogenesis in the hippocampal dentate gyrus of Syn I and Syn II knockout (KO) mice, before (2-months-old) and after (6-months-old) the appearance of the epileptic phenotype. We found that Syns I and II play an important role in the regulation of adult neurogenesis. In juvenile mice, Syn II deletion was associated with a specific decrease in the proliferation of neuronal progenitors, whereas Syn I deletion impaired the survival of newborn neurons. These defects were reverted after the appearance of the epileptic phenotype, with Syn I KO and Syn II KO mice exhibiting significant increases in survival and proliferation, respectively. Interestingly, long-term potentiation dependent on newborn neurons was present in both juvenile Syn mutants while, at later ages, it was only preserved in Syn II KO mice that also displayed an increased expression of brain-derived neurotrophic factor. This study suggests that Syns I and II play a role in adult neurogenesis and the defects in neurogenesis associated with Syn deletion may contribute to the alterations of cognitive functions observed in Syn-deficient mice.
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The Knockout of Synapsin II in Mice Impairs Social Behavior and Functional Connectivity Generating an ASD-like Phenotype.
Cerebral cortex (New York N.Y. : 1991), 2017Co-Authors: Caterina Michetti, Lucian Medrihan, Angela Caruso, Marco Pagani, Mara Sabbioni, Gergely David, Alberto Galbusera, Monica Morini, Alessandro Gozzi, Fabio BenfenatiAbstract:Autism spectrum disorders (ASD) and epilepsy are neurodevelopmental conditions that appear with high rate of co-occurrence, suggesting the possibility of a common genetic basis. Mutations in Synapsin (SYN) genes, particularly SYN1 and SYN2, have been recently associated with ASD and epilepsy in humans. Accordingly, mice lacking Syn1 or Syn2, but not Syn3, experience epileptic seizures and display autistic-like traits that precede the onset of seizures. Here, we analyzed social behavior and ultrasonic vocalizations emitted in 2 social contexts by SynI, SynII, or SynIII mutants and show that SynII mutants display the most severe ASD-like phenotype. We also show that the behavioral SynII phenotype correlates with a significant decrease in auditory and hippocampal functional connectivity as measured with resting state functional magnetic resonance imaging (rsfMRI). Taken together, our results reveal a permissive contribution of Syn2 to the expression of normal socio-communicative behavior, and suggest that Syn2-mediated synaptic dysfunction can lead to ASD-like behavior through dysregulation of cortical connectivity.
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Asynchronous GABA Release Is a Key Determinant of Tonic Inhibition and Controls Neuronal Excitability: A
2016Co-Authors: Lucian Medrihan, Pietro Baldelli, Enrico Ferrea, Barbara Greco, Fabio BenfenatiAbstract:Idiopathic epilepsies have frequently been linked to mutations in voltage-gated channels (channelopathies); recently, mutations in several genes encoding presynaptic proteins have been shown to cause epilepsy in humans and mice, indicating that epilepsy can also be considered a synaptopathy. However, the functional mechanisms by which presynaptic dysfunctions lead to hyperexcitability and sei-zures are not well understood. We show that deletion of Synapsin II (Syn II), a presynaptic protein contributing to epilepsy predisposition in humans, leads to a loss of tonic inhibition in mouse hippocampal slices due to a dramatic decrease in presynaptic asynchronous GABA release. We also show that the asynchronous GABA release reduces postsynaptic cell firing, and the parallel impairment of asynchronous GABA release and tonic inhibition results in an increased excitability at both single-neuron and network levels. Restoring tonic inhibition with THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; gaboxadol), a se-lective agonist of δ subunit-containing GABAA receptors, fully rescues the SynII−/ − epileptic phenotype both ex vivo and in vivo. The results demonstrate a causal relationship between the dynamics of GABA release and the generation of tonic inhibition, and identify a novel mech-anism of epileptogenesis generated by dysfunctions in the dynamics of release that can be effectively targeted by novel antiepileptic strategies
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asynchronous gaba release is a key determinant of tonic inhibition and controls neuronal excitability a study in the Synapsin II mouse
Cerebral Cortex, 2015Co-Authors: Lucian Medrihan, Pietro Baldelli, Fabio Benfenati, Enrico Ferrea, Barbara GrecoAbstract:Idiopathic epilepsies have frequently been linked to mutations in voltage-gated channels (channelopathies); recently, mutations in several genes encoding presynaptic proteins have been shown to cause epilepsy in humans and mice, indicating that epilepsy can also be considered a synaptopathy. However, the functional mechanisms by which presynaptic dysfunctions lead to hyperexcitability and seizures are not well understood. We show that deletion of Synapsin II (Syn II), a presynaptic protein contributing to epilepsy predisposition in humans, leads to a loss of tonic inhibition in mouse hippocampal slices due to a dramatic decrease in presynaptic asynchronous GABA release. We also show that the asynchronous GABA release reduces postsynaptic cell firing, and the parallel impairment of asynchronous GABA release and tonic inhibition results in an increased excitability at both single-neuron and network levels. Restoring tonic inhibition with THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; gaboxadol), a selective agonist of δ subunit-containing GABAA receptors, fully rescues the SynII �/� epileptic phenotype both ex vivo and in vivo. The results demonstrate a causal relationship between the dynamics of GABA release and the generation of tonic inhibition, and identify a novel mechanism of epileptogenesis generated by dysfunctions in the dynamics of release that can be effectively targeted by novel antiepileptic strategies.
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Asynchronous GABA Release Is a Key Determinant of Tonic Inhibition and Controls Neuronal Excitability: A Study in the Synapsin II−/− Mouse
Cerebral cortex (New York N.Y. : 1991), 2014Co-Authors: Lucian Medrihan, Pietro Baldelli, Enrico Ferrea, Barbara Greco, Fabio BenfenatiAbstract:Idiopathic epilepsies have frequently been linked to mutations in voltage-gated channels (channelopathies); recently, mutations in several genes encoding presynaptic proteins have been shown to cause epilepsy in humans and mice, indicating that epilepsy can also be considered a synaptopathy. However, the functional mechanisms by which presynaptic dysfunctions lead to hyperexcitability and seizures are not well understood. We show that deletion of Synapsin II (Syn II), a presynaptic protein contributing to epilepsy predisposition in humans, leads to a loss of tonic inhibition in mouse hippocampal slices due to a dramatic decrease in presynaptic asynchronous GABA release. We also show that the asynchronous GABA release reduces postsynaptic cell firing, and the parallel impairment of asynchronous GABA release and tonic inhibition results in an increased excitability at both single-neuron and network levels. Restoring tonic inhibition with THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; gaboxadol), a selective agonist of δ subunit-containing GABAA receptors, fully rescues the SynII �/� epileptic phenotype both ex vivo and in vivo. The results demonstrate a causal relationship between the dynamics of GABA release and the generation of tonic inhibition, and identify a novel mechanism of epileptogenesis generated by dysfunctions in the dynamics of release that can be effectively targeted by novel antiepileptic strategies.
Ram K Mishra - One of the best experts on this subject based on the ideXlab platform.
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Reduced expression of Synapsin II in a chronic phencyclidine preclinical rat model of schizophrenia.
Synapse (New York N.Y.), 2019Co-Authors: Sharon Thomson, Yuxin Tian, Bailey A. Dyck, Ritesh Daya, Ashley Bernardo, Ram K MishraAbstract:Schizophrenia is a mental disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. Phencyclidine (PCP)-a N-methyl-D-aspartate (NMDA) receptor antagonist-induces symptoms indistinguishable from those of schizophrenia. A reduction of the phosphoprotein Synapsin II has also been implicated in schizophrenia and has a well-known role in the maintenance of the presynaptic reserve pool and vesicle mobilization. This study assessed the behavioral and biochemical outcomes of chronic NMDA receptor antagonism in rodents and its implications for the pathophysiology of schizophrenia. Sprague Dawley rats received saline or chronic PCP (5 mg/kg/day) for 14 days via surgically implanted Alzet® osmotic mini-pumps. Following the treatment period, rats were tested with a series of behavioral paradigms, including locomotor activity, social interaction, and sensorimotor gating. Following behavioral assessment, the medial prefrontal cortex (mPFC) of all rats was isolated for Synapsin II protein analysis. Chronic PCP treatment yielded a hyper-locomotive state (p = 0.0256), reduced social interaction (p = 0.0005), and reduced pre-pulse inhibition (p < 0.0001) in comparison to saline-treated controls. Synapsin IIa (p < 0.0001) and IIb (p < 0.0071) levels in the mPFC of chronically treated PCP rats were reduced in comparison to the saline group. Study results confirm that rats subject to chronic PCP treatment display behavioral phenotypes similar to established preclinical animal models of schizophrenia. Reduction of Synapsin II expression in this context implicates the role of this protein in the pathophysiology of schizophrenia and sheds light on the longer-term consequences of NMDA receptor antagonism facilitated by chronic PCP treatment.
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Role of presynaptic phosphoprotein Synapsin II in schizophrenia.
World journal of psychiatry, 2015Co-Authors: Luke Molinaro, Patricia Hui, Mattea L. Tan, Ram K MishraAbstract:Synapsin II is a member of the neuronal phosphoprotein family. These phosphoproteins are evolutionarily conserved across many organisms and are important in a variety of synaptic functions, including synaptogenesis and the regulation of neurotransmitter release. A number of genome-wide scans, meta-analyses, and genetic susceptibility studies have implicated the Synapsin II gene (3p25) in the etiology of schizophrenia (SZ) and other psychiatric disorders. Further studies have found a reduction of Synapsin II mRNA and protein in the prefrontal cortex in post-mortem samples from schizophrenic patients. Disruptions in the expression of this gene may cause synaptic dysfunction, which can result in neurotransmitter imbalances, likely contributing to the pathogenesis of SZ. SZ is a costly, debilitating psychiatric illness affecting approximately 1.1% of the world's population, amounting to 51 million people today. The disorder is characterized by positive (hallucinations, paranoia), negative (social withdrawal, lack of motivation), and cognitive (memory impairments, attention deficits) symptoms. This review provides a comprehensive summary of the structure, function, and involvement of the Synapsin family, specifically Synapsin II, in the pathophysiology of SZ and possible target for therapeutic intervention/implications.
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change in expression of vesicular protein Synapsin II by chronic treatment with d2 allosteric modulator paopa
Peptides, 2015Co-Authors: Dipannita Basu, Yuxin Tian, Patricia Hui, Jayant Bhandari, Rodney L Johnson, Ram K MishraAbstract:The hallmark symptoms of schizophrenia include profound disturbances in thought, perception, cognition etc., which negatively impacts an individual's quality of life. Current antipsychotic drugs are not effective in treating all symptoms of this disorder, and often cause severe movement and metabolic side effects. Consequently, there remains a strong impetus to develop safer and more efficacious therapeutics for patients, as well as elucidating the etiology of schizophrenia. Previous work in our lab has introduced a novel candidate for the treatment of this disease: the dopamine D2 receptor (D2R) allosteric modulator, 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA). We have previously shown that PAOPA, by selectively modulating D2R, can ameliorate schizophrenia-like symptoms in animal models, although the precise mechanism is presently not understood. Synapsin II is a presynaptic vesicular protein which has been strongly implicated in schizophrenia, as it is reduced in the prefrontal cortex of patients, and knockdown of this protein elicits schizophrenia-like phenotypes in animal models. Given the therapeutic effects of PAOPA and the role of Synapsin II in schizophrenia, the objective of this study was to investigate the effect of chronic administration of PAOPA (45 days) on neuronal Synapsin II protein expression in rodents. Immunoblot results revealed that the Synapsin IIa, but not the IIb isoform, was increased in the dopaminergic regions of the striatum, nucleus accumbens, and medial prefrontal cortex. The results of this study implicate a role for modulation of Synapsin II as a possible therapeutic mechanism of action for potential antipsychotic drug PAOPA.
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Behavioral effects of non-viral mediated RNA interference of Synapsin II in the medial prefrontal cortex of the rat.
Schizophrenia research, 2012Co-Authors: Bailey A. Dyck, Dipannita Basu, Mattea L. Tan, Nancy Thomas, Ritesh P Daya, Christal D R Sookram, Ram K MishraAbstract:Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Researchers have demonstrated reductions in Synapsin II mRNA and protein in post-mortem prefrontal cortex and hippocampus samples from patients with schizophrenia. Synapsin II protein expression has been shown to be regulated by dopamine D(1) and D(2) receptor activation. Furthermore, behavioral testing of the Synapsin II knockout mouse has revealed a schizophrenic-like behavioral phenotype in this mutant strain, suggesting a relationship between dysregulated and/or reduced Synapsin II and schizophrenia. However, it remains unknown the specific regions of the brain of which perturbations in Synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with a selective knock-down of Synapsin II in the medial prefrontal cortex through the use of siRNA technology. Two weeks after continuous infusion of Synapsin II siRNAs, animals were examined for the presence of a schizophrenic-like behavioral phenotype. Our results reveal that rats with selective reductions in medial prefrontal cortical Synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), hyperlocomotion, and reduced social behavior. These results implicate a role for decreased medial prefrontal cortical Synapsin II levels in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that increasing Synapsin II levels in the medial prefrontal cortex may potentially serve as a novel therapeutic target for this devastating disorder.
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Medial prefrontal cortical Synapsin II knock-down induces behavioral abnormalities in the rat: examining Synapsin II in the pathophysiology of schizophrenia.
Schizophrenia Research, 2011Co-Authors: Bailey A. Dyck, Michael G.r. Beyaert, Mark A. Ferro, Ram K MishraAbstract:Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Studies have demonstrated reductions in Synapsin II mRNA and protein in medial prefrontal cortical post-mortem samples from patients with schizophrenia, genetic associations between Synapsin II and schizophrenia, and Synapsin II protein regulation by dopamine receptor activation. Collectively, this research indicates a relationship between Synapsin II dysregulation and schizophrenia; however, it remains unknown whether perturbations in Synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with selective knock-down of Synapsin II in the medial prefrontal cortex. After continuous infusion of Synapsin II antisense sequences, animals were examined for the presence of schizophrenic-like behavioral phenotypes and assessed on the response to clinically relevant antipsychotic drugs. Our results indicate that rats with selective reductions in medial prefrontal cortical Synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), reduced social behavior, and hyperlocomotion, which are corrected by the atypical antipsychotic drug olanzapine. Additionally, Synapsin II knock-down disrupts serial search efficiency. These behavioral changes are accompanied by reductions in vesicular neurotransmitter transporter protein concentrations for glutamate (VGLUT1 and VGLUT2) and GABA (VGAT), without affecting dopamine (VMAT2). These results implicate a causal role for decreased Synapsin II in the medial prefrontal cortex in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that Synapsin II may potentially serve as a novel therapeutic target for this disorder.
Lars Etholm - One of the best experts on this subject based on the ideXlab platform.
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Sensitive and critical periods in the development of handling induced seizures in mice lacking Synapsins: Differences between Synapsin I and Synapsin II knockouts
Experimental neurology, 2013Co-Authors: Lars Etholm, Elma Bahonjic, Paul HeggelundAbstract:Abstract Mice lacking either Synapsin I or Synapsin II develop handling induced seizures from around two months of age. In mice lacking Synapsin I (Synapsin 1 knock-out mice, Syn1KO mice) such seizures can either consist of mild myoclonic jerks or of fully developed generalized tonic–clonic seizures, and the two seizure types are quite evenly distributed. In mice lacking Synapsin II (Synapsin 2 knock-out mice, Syn2KO mice) all seizures are in the form of generalized tonic–clonic seizures. Through the use of specialized animal rearing procedures whereby human–animal interaction was minimized (minimal handling procedures), this study investigated effects of handling also prior to the emergence of actual seizures. The effect of minimal handling procedures was significant in both genotypes, but most pronounced in Syn1KO mice. In this genotype, minimal handling reduced the frequency of mild seizures, and completely eliminated generalized tonic–clonic seizures when the animals were tested with regular handling at 4 1/2 months of age. Neither seizure frequency nor generalized tonic–clonic seizures could be re-established through regular handling from 4 1/2 to 8 months. This suggests that the period up to 4 1/2 months constitute a sensitive period for seizures in general, and a critical period for generalized tonic–clonic seizures in this genotype. In Syn2KO mice minimal handling did not remove generalized tonic–clonic seizures, as such seizures were present when handling was introduced at 4 1/2 months. We found an initial reduction of seizure frequency, but the seizure frequency eventually reached levels seen in mice kept under regular handling regimes. Thus, it is unlikely that the period up to 4 1/2 months is a sensitive period in the Syn2KO genotype.
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Neuroethologically delineated differences in the seizure behavior of Synapsin 1 and Synapsin 2 knock-out mice
Epilepsy research, 2012Co-Authors: Lars Etholm, Hung-teh Kao, Elma Bahonjic, S.i. Walaas, Paul HeggelundAbstract:The highly homologous nerve terminal phosphoproteins Synapsin I and Synapsin II have been linked to the pathogenesis of epilepsy through associations between Synapsin gene mutations and epileptic disease in humans and to the observation of handling induced seizures in mice genetically depleted of one or both of these proteins. Whereas seizure behavior in mice lacking both Synapsin I and Synapsin II is well characterized, the seizure behavior in mice lacking either is less well studied. Through so called neuroethologically based analyses of fully established seizure behavior in Synapsin 1 and 2 knock-out mice (Syn1KO and Syn2KO mice) aged 4 1/2 months, this study reveals significant differences in the seizure behavior of the two genotypes: whereas Syn1KO mice show both partial and generalized forebrain seizure activity, Syn2KO mice show only fully generalized forebrain seizures. Analysis of seizure behavior at earlier stages shows that the mature seizure pattern in Syn2KO mice establishes rapidly from the age of ∼2 months, when Syn1KO partial seizures are rare, and Syn1KO generalized seizures are almost absent. The specific behavioral phenotypes of the two strains suggest that the slight differences in structure, function and expression of these highly related proteins could be important factors during seizure generating neural activity.
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Electroencephalographic characterization of seizure activity in the Synapsin I/II double knockout mouse.
Brain research, 2011Co-Authors: Lars Etholm, Henrik Lindén, Torsten Eken, Paul HeggelundAbstract:We present a detailed comparison of the behavioral and electrophysiological development of seizure activity in mice genetically depleted of Synapsin I and Synapsin II (SynDKO mice), based on combined video and surface EEG recordings. SynDKO mice develop handling-induced epileptic seizures at the age of 2 months. The seizures show a very regular behavioral pattern, where activity is initially dominated by truncal muscle contractions followed by various myoclonic elements. Whereas seizure behavior goes through clearly defined transitions, cortical activity as reflected by EEG recordings shows a more gradual development with respect to the emergence of different EEG components and the frequency of these components. No EEG pattern was seen to define a particular seizure behavior. However, myoclonic activity was characterized by more regular patterns of combined sharp waves and spikes. Where countable, the number of myoclonic jerks was significantly correlated to the number of such EEG complexes. Furthermore, some EEG recordings revealed epileptic regular discharges without clear behavioral seizure correlates. Our findings suggest that seizure behavior in SynDKO mice is not solely determined by cortical activity but rather reflects interplay between cortical activity and activity in other brain regions.
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seizure elements and seizure element transitions during tonic clonic seizure activity in the Synapsin i II double knockout mouse a neuroethological description
Epilepsy & Behavior, 2009Co-Authors: Lars Etholm, Paul HeggelundAbstract:Inactivation of genes for the synaptic terminal proteins Synapsin I and Synapsin II leads to development of epileptic seizures in mice (Syn-DKO mice) in which no other behavioral abnormalities or any gross anatomical brain deformities have been reported. In humans, mutated Synapsin I is associated with epilepsy. Thus, the Syn-DKO mouse might model human seizure development. Here we describe a neuroethological analysis of behavioral elements and relationships between these elements during seizures in Syn-DKO mice. The seizure elements belong to one of three clusters each characterized by specific patterns of activity: truncus-dominated elements, myoclonic elements, and running-fit activity. The first two clusters, constituting the majority of seizural activity, evolve quite differently during ongoing seizure activity. Whereas truncus-dominated elements unfold in a strict sequence, the myoclonic elements wax and wane more independently, once myoclonic activity has started. These differences may point to neurobiological mechanisms relevant to both rodent and human epilepsies.
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Seizure elements and seizure element transitions during tonic–clonic seizure activity in the Synapsin I/II double knockout mouse: A neuroethological description
Epilepsy & behavior : E&B, 2009Co-Authors: Lars Etholm, Paul HeggelundAbstract:Inactivation of genes for the synaptic terminal proteins Synapsin I and Synapsin II leads to development of epileptic seizures in mice (Syn-DKO mice) in which no other behavioral abnormalities or any gross anatomical brain deformities have been reported. In humans, mutated Synapsin I is associated with epilepsy. Thus, the Syn-DKO mouse might model human seizure development. Here we describe a neuroethological analysis of behavioral elements and relationships between these elements during seizures in Syn-DKO mice. The seizure elements belong to one of three clusters each characterized by specific patterns of activity: truncus-dominated elements, myoclonic elements, and running-fit activity. The first two clusters, constituting the majority of seizural activity, evolve quite differently during ongoing seizure activity. Whereas truncus-dominated elements unfold in a strict sequence, the myoclonic elements wax and wane more independently, once myoclonic activity has started. These differences may point to neurobiological mechanisms relevant to both rodent and human epilepsies.
