Many cellular functions are regulated by calcium (Ca2+) signals that are generated by different signaling pathways. One of these is the inositol 1,4,5-trisphosphate/calcium (InsP3/Ca2+) signaling p...

/pdf/the-inositol-trisphosphate-calcium-signaling-pathway-in-42nqzabn60.pdf

The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease

Disrupted in schizophrenia 1 (DISC1) is an important hub protein, forming multimeric complexes by self-association and interacting with a large number of synaptic and cytoskeletal molecules. The synaptic location of DISC1 in the adult brain suggests a role in synaptic plasticity, and indeed, a number of studies have discovered synaptic plasticity impairments in a variety of different DISC1 mutants. This review explores the possibility that DISC1 is an important molecule for organizing proteins involved in synaptic plasticity and examines why mutations in DISC1 impair plasticity. It concentrates on DISC1's role in interacting with synaptic proteins, controlling dendritic structure and cellular trafficking of mRNA, synaptic vesicles and mitochondria. N-terminal directed mutations appear to impair synaptic plasticity through interactions with phosphodiesterase 4B (PDE4B) and hence protein kinase A (PKA)/GluA1 and PKA/cAMP response element-binding protein (CREB) signalling pathways, and affect spine structure through interactions with kalirin 7 (Kal-7) and Rac1. C-terminal directed mutations also impair plasticity possibly through altered interactions with lissencephaly protein 1 (LIS1) and nuclear distribution protein nudE-like 1 (NDEL1), thereby affecting developmental processes such as dendritic structure and spine maturation. Many of the same molecules involved in DISC1's cytoskeletal interactions are also involved in intracellular trafficking, raising the possibility that impairments in intracellular trafficking affect cytoskeletal development and vice versa. While the multiplicity of DISC1 protein interactions makes it difficult to pinpoint a single causal signalling pathway, we suggest that the immediate-term effects of N-terminal influences on GluA1, Rac1 and CREB, coupled with the developmental effects of C-terminal influences on trafficking and the cytoskeleton make up the two main branches of DISC1's effect on synaptic plasticity and dendritic spine stability.

/pdf/mechanisms-underlying-the-role-of-disc1-in-synaptic-51o8lsomdq.pdf

Mechanisms underlying the role of DISC1 in synaptic plasticity

The adult human brain consists of approximately a hundred billion neurons, which are connected via synapses. The pattern and strength of the synaptic connections are constantly changing (synaptic plasticity), and these changes are considered to underlie learning, memory, and personality. Many psychiatric disorders have been related to disturbances in synaptogenesis and subsequent plasticity. In this review, we summarize findings of synaptic disturbance and its involvement in the pathogenesis and/or pathophysiology of psychiatric disorders. We will focus on schizophrenia, because this condition has a high proven heritability, which offers more unambiguous insights into the biological origins of not only schizophrenia but also related psychiatric disorders. To demonstrate the involvement of synaptopathy in psychiatric disorders, we discuss what knowledge is missing at the circuits level, and what new technologies are needed to achieve a comprehensive understanding of synaptopathy in psychiatric disorders.

Synaptic functions and their disruption in schizophrenia: From clinical evidence to synaptic optogenetics in an animal model.

Using a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltage-dependent potassium channel subunit Kv1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of Kv1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to Kv1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity. SIGNIFICANCE STATEMENT Schizophrenia is a profoundly disabling psychiatric illness with a devastating impact not only upon the afflicted but also upon their families and the broader society. Although the underlying causes of schizophrenia remain poorly understood, a growing body of studies has identified and strongly implicated various specific risk genes in schizophrenia pathogenesis. Here, using a genetic mouse model, we explored the impact of one of the most highly penetrant schizophrenia risk genes, DISC1, upon the medial prefrontal cortex, the region believed to be most prominently dysfunctional in schizophrenia. We found substantial derangements in both neuronal excitability and short-term synaptic plasticity—parameters that critically govern neural circuit information processing—suggesting that similar changes may critically, and more broadly, underlie the neural computational dysfunction prototypical of schizophrenia.

https://www.jneurosci.org/content/jneuro/37/15/4158.full.pdf

Alteration of Neuronal Excitability and Short-Term Synaptic Plasticity in the Prefrontal Cortex of a Mouse Model of Mental Illness.

DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia 1

DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia 1.

Disrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major psychiatric disorders, including schizophrenia. DISC1 has been implicated in neurodevelopment in relation to scaffolding signal complexes. Here we used proteomic analysis to screen for DISC1 interactors and identified several RNA-binding proteins, such as hematopoietic zinc finger (HZF), that act as components of RNA-transporting granules. HZF participates in the mRNA localization of inositol-1,4,5-trisphosphate receptor type 1 (ITPR1), which plays a key role in synaptic plasticity. DISC1 colocalizes with HZF and ITPR1 mRNA in hippocampal dendrites and directly associates with neuronal mRNAs, including ITPR1 mRNA. The binding potential of DISC1 for ITPR1 mRNA is facilitated by HZF. Studies of Disc1-knockout mice have revealed that DISC1 regulates the dendritic transport of Itpr1 mRNA by directly interacting with its mRNA. The DISC1-mediated mRNA regulation is involved in synaptic plasticity. We show that DISC1 binds ITPR1 mRNA with HZF, thereby regulating its dendritic transport for synaptic plasticity.

Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity

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Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity