Targeting the Hippocampal Mossy Fiber Synapse for the Treatment of Psychiatric Disorders

Kobayashi, Katsunori

doi:10.1007/s12035-008-8049-5

Cited by 63 publications

(55 citation statements)

References 194 publications

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“…The prominent synaptic facilitation plays a critical role in regulation of the CA3 neuronal activity and plasticity by MF (9,10). The dematuration affected both of these important physiological properties of mature GCs, thereby potentially impeding proper functioning of the adult hippocampus (43). Similar changes in GC functions and/or in the state of GC maturation have been demonstrated in mice disrupted for the gene encoding alpha-CaMKII (27), brain-derived neurotrophic factor (44), or the glutamate receptor subunit GluK2/GluR6 (10,45).…”

Section: Discussionmentioning

confidence: 99%

Reversal of hippocampal neuronal maturation by serotonergic antidepressants

Kobayashi

Ikeda

Sakai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Serotonergic antidepressant drugs have been commonly used to treat mood and anxiety disorders, and increasing evidence suggests potential use of these drugs beyond current antidepressant therapeutics. Facilitation of adult neurogenesis in the hippocampal dentate gyrus has been suggested to be a candidate mechanism of action of antidepressant drugs, but this mechanism may be only one of the broad effects of antidepressants. Here we show a distinct unique action of the serotonergic antidepressant fluoxetine in transforming the phenotype of mature dentate granule cells. Chronic treatments of adult mice with fluoxetine strongly reduced expression of the mature granule cell marker calbindin. The fluoxetine treatment induced active somatic membrane properties resembling immature granule cells and markedly reduced synaptic facilitation that characterizes the mature dentate-to-CA3 signal transmission. These changes cannot be explained simply by an increase in newly generated immature neurons, but best characterized as "dematuration" of mature granule cells. This granule cell dematuration developed along with increases in the efficacy of serotonin in 5-HT 4 receptor-dependent neuromodulation and was attenuated in mice lacking the 5-HT 4 receptor. Our results suggest that serotonergic antidepressants can reverse the established state of neuronal maturation in the adult hippocampus, and up-regulation of 5-HT 4 receptor-mediated signaling may play a critical role in this distinct action of antidepressants. Such reversal of neuronal maturation could affect proper functioning of the mature hippocampal circuit, but may also cause some beneficial effects by reinstating neuronal functions that are lost during development. dentate gyrus | development | mossy fiber | serotonin receptor | serotonin reuptake inhibitor

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Section: Discussionmentioning

confidence: 99%

Reversal of hippocampal neuronal maturation by serotonergic antidepressants

Kobayashi

Ikeda

Sakai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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188

275

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“…Given that the DG is the site of highest DISC1 expression in the adult brain (11) and has been implicated in SCHZ pathophysiology (12,35), we examined the development, maturation, and excitability of dentate GCs as well as synaptic transmission and plasticity in the MF/CA3 circuit. We elucidated the impact of the pathogenic DISC1 mutation by applying an array of morphological, neurophysiological, biochemical, and cellular assays to an etiologically valid mouse model of this mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Although the pattern of MF lamination has not been explicitly probed in patients with SCHZ, one study has reported lower numerical density of MFTs in CA3 (44), and another study showed lighter overall staining with an MF specific marker (45) consistent with changes occurring in this pathway. More broadly, neuropathological studies have found a number of variable and modest disturbances in the overall DG-CA3 region, including reduced dendritic arborization (13,14), implicating this region in SCHZ pathogenesis (12,35).…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal neuronal development and function of the DG has been proposed as a risk factor for a number of psychiatric disorders, including depression and SCHZ (12), and thus, it could contribute to the increased rates of SCHZ and mood disorders found in the Scottish pedigree. Neuropathological studies of patients with SCHZ have found a number of variable and modest cytoarchitectural disturbances in the DG-CA3 regions, including impaired dendritic arborization (13,14), as well as alterations in synaptic density and mossy fibers (MFs) terminal structure (12). DG receives, as a primary input, sensory information from the entorhinal cortex and projects exclusively to the CA3 region of the HPC, acting as an important processor of sensory input for integration in hippocampal networks.…”

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confidence: 99%

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Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Kvajo

McKellar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophreniapredisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growthpromoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations. psychiatric disease | rare mutation | mouse model T he schizophrenia (SCHZ) susceptibility gene DISC1 was identified through a balanced chromosomal translocation (1;11)(q42.1;q14.3) segregating with SCHZ and mood disorders in a large Scottish pedigree. This is the only confirmed disease risk allele within the DISC1 locus. The biology of DISC1 is being interrogated with a variety of approaches, such as acute RNAimediated gene knockdown (1-4), overexpression of truncated forms of the human DISC1 (5, 6), and chemical mutagenesis (7). Although they provide information about potential pathways related to DISC1, these approaches are not meant to recapitulate the integrated effects of the pathogenic translocation, and the relevance of these findings to SCHZ pathogenesis remains uncertain.We used a disease-focused knockin approach to introduce a truncating lesion in the endogenous murine Disc1 ortholog designed to model the effects of the (1;11) translocation (Mouse Genome Informatics nomenclature Disc1 Tm1Kara ) (8, 9). Although the divergence in the human and mouse Disc1 gene does not allow an exact replication of the human translocation, this mouse model approximates very closely the Scottish mutation. One advantage of our approach is that it retains endogenous levels as well as spatial and temporal patterns of Disc1 expression, and it preserves short N-terminal isoforms that are presumably unaffected by the Scottish translocation and seem to be expressed at relatively higher levels in the hippocampus (HPC) of patients with SCHZ (10). A comprehensive behavioral analysis has shown that Disc1 Tm1Kara mice display a unique profile of cognitive impairments, including specific and robust deficiencies in working memory (WM) tests (8, 9), which may relate to similar cognitive deficits prominent in psychotic disorders.DISC1 is...

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“…Stress, which is generally thought to precipitate psychiatric disorders including depression, changes the structure and functions of the mossy fiber synapse (Chen et al, 2010;Kobayashi, 2010;Magariños et al, 1997). These lines of evidence suggest that the mossy fiber synapse could be an important target for SSRIs and other antidepressant drugs (Kobayashi, 2009(Kobayashi, , 2010.…”

Section: Introductionmentioning

confidence: 99%

Chronic Fluoxetine Selectively Upregulates Dopamine D1-Like Receptors in the Hippocampus

Kobayashi

Haneda

Higuchi³

et al. 2012

Neuropsychopharmacol

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The dentate gyrus of the hippocampus has been implicated in mechanisms of action of selective serotonin reuptake inhibitors (SSRIs). We have recently demonstrated that the SSRI fluoxetine can reverse the state of maturation of the adult dentate granule cells and enhances serotonin 5-HT 4 receptor-mediated synaptic potentiation at the synapses formed by their mossy fiber axons. Here, we show that fluoxetine can induce long-lasting enhancement of dopaminergic modulation at the mossy fiber synapse. Synaptic responses arising from the mossy fiber-CA3 pyramidal cell synapse were recorded using acute mouse hippocampal slices. Dopamine potentiates mossy fiber synaptic transmission by activating D 1 -like receptors. Chronic fluoxetine treatment induced a prominent increase in the magnitude of dopamine-induced synaptic potentiation, and this effect was maintained at least up to 1 month after withdrawal of fluoxetine. Quantitative autoradiography revealed that binding of the D 1 -like receptor ligand [ 3 H]SCH23390 was selectively increased in the dentate gyrus and along the mossy fiber in fluoxetine-treated mice. However, binding of the 5-HT 4 receptor ligand [ 3 H]GR113808 was not significantly changed. These results suggest that chronic fluoxetine enhanced the dopaminergic modulation at least in part by upregulating expression of D 1 -like receptors, while the enhanced serotonergic modulation may be mediated by modifications of downstream signaling pathways. These enhanced monoaminergic modulations would greatly increase excitatory drive to the hippocampal circuit through the dentate gyrus. The highly localized upregulation of D 1 -like receptors further supports the importance of the dentate gyrus in the mechanism of action of SSRIs.

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Targeting the Hippocampal Mossy Fiber Synapse for the Treatment of Psychiatric Disorders

Cited by 63 publications

References 194 publications

Reversal of hippocampal neuronal maturation by serotonergic antidepressants

Reversal of hippocampal neuronal maturation by serotonergic antidepressants

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Chronic Fluoxetine Selectively Upregulates Dopamine D1-Like Receptors in the Hippocampus

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