Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia

Kolomeets, Natalya S.; Orlovskaya, D.D.; Na, Uranova

doi:10.1002/syn.20405

Cited by 96 publications

(76 citation statements)

References 56 publications

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“…17,[76][77][78][79] The CA2/3 region has close functional connections to many other brain regions including the hypothalamus, septal nucleus, 80 subiculum, 81 and the CA1 region of the hippocampus. 82 Thus, while we confirm and extend the knowledge implicating the hippocampus and the CA2/3 region in schizophrenia 20,83 and bipolar disorder, changes in this region will have widespread consequences within the brain.…”

Section: Commentsupporting

confidence: 72%

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3

Föcking

Dicker²,

English³

et al. 2011

Arch Gen Psychiatry

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Section: Commentsupporting

confidence: 72%

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3

Föcking

Dicker²,

English³

et al. 2011

Arch Gen Psychiatry

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“…Although additional experiments are needed, these observations suggest that DISC1 may regulate the maturation or stability of these boutons. It is interesting to note that a recent EM analysis of mossy fiber boutons from postmortem schizophrenic brains revealed that, although mossy fiber boutons from schizophrenics are the same size as in controls, the boutons in schizophrenic brains have a reduction in both spine and synaptic contact number (30,31), suggesting that destabilization of the mossy fiber boutons may be important for the pathology of schizophrenia in general.…”

Section: Discussionmentioning

confidence: 99%

Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain

Faulkner

Jang

Liu

et al. 2008

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

192

179

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New neurons are continuously generated in restricted regions of the adult mammalian brain. Although these adult-born neurons have been shown to receive synaptic inputs, little is known about their synaptic outputs. Using retrovirus-mediated birth-dating and labeling in combination with serial section electron microscopic reconstruction, we report that mossy fiber en passant boutons of adult-born dentate granule cells form initial synaptic contacts with CA3 pyramidal cells within 2 weeks after their birth and reach morphologic maturity within 8 weeks in the adult hippocampus. Knockdown of Disrupted-in-Schizophrenia-1 (DISC1) in newborn granule cells leads to defects in axonal targeting and development of synaptic outputs in the adult brain. Together with previous reports of synaptic inputs, these results demonstrate that adultborn neurons are fully integrated into the existing neuronal circuitry. Our results also indicate a role for DISC1 in presynaptic development and may have implications for the etiology of schizophrenia and related mental disorders.adult neurogenesis ͉ synaptogenesis ͉ DISC1 ͉ hippocampus ͉ axon guidance N ew neurons generated in the adult mammalian brain are believed to contribute to specific brain functions (1-4). Although the existence of synaptic inputs to the dendrites of adultborn neurons has been well documented (5-12), there is a lack of knowledge regarding whether and when the axons of new neurons form synaptic outputs. This makes the claim of their full integration into existing neural circuitry premature. Newborn dentate granule cells (DGCs) in the adult hippocampus are known to extend their axons into the CA3 subfield (8,13,14), but it is unclear whether typical synaptic structures are formed by these new neurons in vivo. Using a retrovirus expressing EGFP to birth-date and label adultborn neurons (5,8,15), we examined the development of their axons and synaptic outputs by confocal and quantitative immunoelectron microscopy (EM) with 3D reconstruction of labeled boutons (15-17). We show that the axons of adult-born DGCs form typical mossy fiber bouton synaptic complexes with CA3 pyramidal cells within 8 weeks.To explore the molecular mechanisms regulating axonal outputs by new neurons in the adult brain, we examined the role of disc1, a susceptibility gene for schizophrenia and other major mental illness (18)(19)(20). DISC1 (Disrupted-in-Schizophrenia-1) is highly expressed in the developing and adult hippocampus (21), and its expression pattern, together with the recent identification of a large number of DISC1 interacting proteins (22), strongly suggests potential roles for DISC1 in regulating neuronal development (18)(19)(20). The in vivo cellular functions of DISC1, however, are not completely understood. Interfering with DISC1 function in utero leads to defects in embryonic cortical neuronal migration and dendritic orientation (23). Perturbation of DISC1 functions in genetically modified mice by deleting a subset of DISC1 isoforms leads to some defects in migration and dendri...

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“…There is also evidence of differential activation of the SPBs and IPBs of the DG (43), and altered segregation of the SP and IP blades may change the respective connectivities of these blades with CA3. 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%

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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Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia

Cited by 96 publications

References 56 publications

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3

Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain

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

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