Synapsin II knockout mice show sensorimotor gating and behavioural abnormalities similar to those in the phencyclidine-induced preclinical animal model of schizophrenia

Dyck, Bailee A.; Skoblenick, Kevin; Castellano, Jessica M.; Ki, Kitty; Thomas, Nancy; Mishra, Ram K.

doi:10.1016/j.schres.2007.08.026

Cited by 27 publications

(13 citation statements)

References 9 publications

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“…Moreover, clinical genetic studies have identified genes encoding presynaptic proteins as risk factors for schizophrenia (Karson et al, 1999; Mirnics et al, 2000; Tachikawa et al, 2001; Chen et al, 2004; Lee et al, 2005; Muller et al, 2005; Verma et al, 2005; Kirov et al, 2008; Sudhof, 2008; Walsh et al, 2008; Rujescu et al, 2009). Consistent with these findings, mutation of genes encoding presynaptic proteins has resulted in mouse models relevant to schizophrenia (Drew et al, 2007; Dyck et al, 2007, 2009; Etherton et al, 2009). Thus, we hypothesized that deletion or mutation of the presynaptic protein RIM1α, and its binding partners Rab3A and synaptotagmin, would lead to schizophrenia-related behavioural abnormalities (Powell and Miyakawa, 2006).…”

Section: Introductionsupporting

confidence: 53%

RIM1α and Interacting Proteins Involved in Presynaptic Plasticity Mediate Prepulse Inhibition and Additional Behaviors Linked to Schizophrenia

Blundell¹,

Kaeser²,

Südhof³

et al. 2010

J. Neurosci.

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Several presynaptic proteins involved in neurotransmitter release in the CNS have been implicated in schizophrenia in human clinical genetic studies, in postmortem studies, and in studies of putative animal models of schizophrenia. The presynaptic protein RIM1␣ mediates presynaptic plasticity and cognitive function. We now demonstrate that mice deficient in RIM1␣ exhibit abnormalities in multiple schizophrenia-relevant behavioral tasks including prepulse inhibition, response to psychotomimetic drugs, and social interaction. These schizophrenia-relevant behavioral findings are relatively selective to RIM1␣-deficient mice, as mice bearing mutations in the RIM1␣ binding partners Rab3A or synaptotagmin 1 only show decreased prepulse inhibition. In addition to RIM1␣'s involvement in multiple behavioral abnormalities, these data suggest that alterations in presynaptic forms of short-term plasticity are linked to alterations in prepulse inhibition, a measure of sensorimotor gating.

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Section: Introductionsupporting

confidence: 53%

RIM1α and Interacting Proteins Involved in Presynaptic Plasticity Mediate Prepulse Inhibition and Additional Behaviors Linked to Schizophrenia

Blundell¹,

Kaeser²,

Südhof³

et al. 2010

J. Neurosci.

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“…Recently, we have also shown that synapsin II knockout mice exhibit behavioral abnormalities similar to preclinical animal models of schizophrenia produced by treatment with dopaminergic agents, such as D-amphetamine (Dyck et al 2007(Dyck et al , 2009). However, the transcription factors involved in the regulation of synapsin II gene expression by dopaminergic ligands have not been established.…”

Section: Discussionmentioning

confidence: 94%

Role of AP-2α Transcription Factor in the Regulation of Synapsin II Gene Expression by Dopamine D1 and D2 Receptors

Skoblenick

Argintaru

et al. 2009

J Mol Neurosci

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Synapsins are a family of neuron-specific phosphoproteins involved in synaptic vesicle docking, synaptogenesis, and synaptic plasticity. Previous studies have reported an increase in synapsin II protein by dopaminergic agents in the striatum, medial prefrontal cortex, and nucleus accumbens. This study investigated the mechanistic pathway involved in synapsin II regulation by dopaminergic drugs using primary midbrain neurons to determine which of several transcription factors regulates synapsin II expression. Protein kinase A (PKA) participation in the signaling pathway was examined using selective PKA inhibitors, which reduced synapsin II expression in cell cultures while dopaminergic agents were unable to increase synapsin II in the presence of the PKA inhibitor. Transcription factor involvement was further investigated using separate cultures treated with antisense deoxyoligonucleotides (ADONs) against the following transcription factors: activating protein 2 alpha (AP-2alpha), early growth response factor 1 (EGR-1), or polyoma enhancer activator-3 (PEA-3). Selective knockdown of AP-2alpha by ADONs reduced synapsin II levels, whereas treatment with EGR-1 and PEA-3 ADONs did not affect synapsin II expression. Furthermore, dopaminergic agents were no longer able to influence synapsin II concentrations following AP-2alpha knockdown. Collectively, these results indicate that a cyclic adenosine-3',5'-monophosphate/PKA-dependent mechanism involving the AP-2alpha transcription factor is likely responsible for the increase in neuronal synapsin II following dopamine D1 receptor stimulation or dopamine D2 receptor inhibition.

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“…In another study, a decrease in SynII gene expression in postmortem brain tissue of BPD patients might be explained by the presence of hypomethylated I CpG islands found in this gene [32]. The findings in humans are, in part, reproducible in animal models because a Syn II knock-out (KO) animal model results in a schizophrenic-like phenotype [28–30]. The third member of the family, synapsin 3, has also been implicated in SCZ because a decrease in its expression was observed in the prefrontal cortex of individuals with SCZ [33].…”

Section: Presynaptic Proteinsmentioning

confidence: 99%

Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

2017

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Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype.

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Synapsin II knockout mice show sensorimotor gating and behavioural abnormalities similar to those in the phencyclidine-induced preclinical animal model of schizophrenia

Cited by 27 publications

References 9 publications

RIM1α and Interacting Proteins Involved in Presynaptic Plasticity Mediate Prepulse Inhibition and Additional Behaviors Linked to Schizophrenia

RIM1α and Interacting Proteins Involved in Presynaptic Plasticity Mediate Prepulse Inhibition and Additional Behaviors Linked to Schizophrenia

Role of AP-2α Transcription Factor in the Regulation of Synapsin II Gene Expression by Dopamine D1 and D2 Receptors

Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

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