Reduced Density of Cholinergic Interneurons in the Ventral Striatum in Schizophrenia: An In Situ Hybridization Study

Holt, Daphne J.; Bachus, Susan E.; Hyde, Thomas M.; Wittie, Michael; Herman, Mary M.; Vangel, Mark; Saper, Clifford B.; Kleinman, Joel E.

doi:10.1016/j.biopsych.2005.04.007

Cited by 70 publications

(59 citation statements)

References 49 publications

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“…It also remains unclear, if these changes in the muscarinic cholinergic system in schizophrenia are of a primary or of a secondary nature. 78,192 However, the 'muscarinic hypothesis of schizophrenia' should not be seen in isolation but as an addition to existing theories on schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have so far assessed the distribution of cholinergic neurons in schizophrenia. A reduced number of cholinergic interneurons was described in the ventral striatum in schizophrenia, 77,78 but the distribution of mesopontine cholinergic neurons has yielded conflicting results. [79][80][81] Analyzing the density of muscarinic receptors, an early study using 3 H-QNB reported a significant reduction in the level of muscarinic receptor binding in the frontal cortex of subjects with schizophrenia compared to healthy controls.…”

Section: Post-mortem Cns Studiesmentioning

confidence: 99%

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Towards a muscarinic hypothesis of schizophrenia

Raedler

Bymaster

Tandon³

et al. 2006

Mol Psychiatry

247

211

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Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including preclinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Post-mortem Cns Studiesmentioning

confidence: 99%

Towards a muscarinic hypothesis of schizophrenia

Raedler

Bymaster

Tandon³

et al. 2006

Mol Psychiatry

247

211

View full text Add to dashboard Cite

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“…Lower density of cholinergic interneurons was reported in the ventral striatum (corresponding to the NAc in our study) in schizophrenia (Holt et al, 2005), lower NOS-positive interneurons in the putamen (Lauer et al, 2005), and lower total neuron number in the caudate (with no alterations in density) (Kreczmanski et al, 2007). We remain cautious in interpreting our findings in the context of such literature, as anatomical locations of the studies might differ, and it is unclear whether SNARE protein distribution is the same in all synapses (Garbelli et al, 2008).…”

Section: Snare Protein Levelsmentioning

confidence: 95%

A Novel Mechanism and Treatment Target for Presynaptic Abnormalities in Specific Striatal Regions in Schizophrenia

Barakauskas

Beasley

Barr

et al. 2010

Neuropsychopharmacol

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Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of proteinprotein interactions are limited. We extended these investigations to the striatal regions (such as the nucleus accumbens, ventromedial caudate (VMC), and dorsal caudate) relevant to disease symptoms. In addition to measuring SNARE protein levels, we studied SNARE protein-protein interactions using a novel ELISA method. The possible effect of antipsychotic treatment was investigated in parallel in the striatum of rodents that were administered haloperidol and clozapine. In schizophrenia samples, compared with controls, SNAP-25 was 32% lower (P ¼ 0.015) and syntaxin was 26% lower (P ¼ 0.006) in the VMC. In contrast, in the same region, SNARE protein-protein interactions were higher in schizophrenia (P ¼ 0.008). Confocal microscopy of schizophrenia and control VMC showed qualitatively similar SNARE protein immunostaining. Haloperidol treatment of rats increased levels of SNAP-25 (mean 24%, P ¼ 0.003), syntaxin (mean 18%, P ¼ 0.010), and VAMP (mean 16%, P ¼ 0.001), whereas clozapine increased only the VAMP level (mean 13%, P ¼ 0.004). Neither drug altered SNARE protein-protein interactions. These results indicate abnormalities of amount and interactions of proteins directly related to presynaptic function in the VMC in schizophrenia. SNARE proteins and their interactions may be a novel target for the development of therapeutics.

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“…Besides decrements in receptors for ACh, one group has observed a reduction in numbers of cholinergic interneurons in the ventral striatum (Holt et al, 1999(Holt et al, , 2005, but not in other striatal regions. However, cortical cholinesterase and ChAT activity is not reduced in the brains of patients with schizophrenia (Haroutunian et al, 1994).…”

Section: Deficits In Cholinergic Innervationmentioning

confidence: 99%

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

Berman

Talmage

Role

2007

International Review of Neurobiology

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Central cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central cholinergic circuits are resistant to simplification-particularly when one tries to parse the contributions of various classes of cholinergic receptors to disease related phenomena-the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of cholinergic activity may modulate corticostriatal circuits affected in schizophrenia.

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Reduced Density of Cholinergic Interneurons in the Ventral Striatum in Schizophrenia: An In Situ Hybridization Study

Cited by 70 publications

References 49 publications

Towards a muscarinic hypothesis of schizophrenia

Towards a muscarinic hypothesis of schizophrenia

A Novel Mechanism and Treatment Target for Presynaptic Abnormalities in Specific Striatal Regions in Schizophrenia

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

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