Synaptic differences in the postmortem striatum of subjects with schizophrenia: A stereological ultrastructural analysis

Roberts, Rosalinda C.; Roche, Joy K.; Conley, Robert R.

doi:10.1002/syn.20144

Cited by 49 publications

(47 citation statements)

References 121 publications

(105 reference statements)

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“…This is consistent with findings in the dorsal striatum which also found an increase in AS synapses in SZ. 6 In agreement with this finding is evidence for an increased expression of the excitatory PSD protein SAP90/PSD-95-associated protein 1 (SAPAP1) in the NAcc in postmortem SZ. 23 Rodent models of SZ also exhibit increased indices of glutamatergic-type input in the NAcc; rats treated with psychotomimetics have increased mRNA expression of excitatory PSD genes, 23,24 and increased dendritic spine density in the NAcc, [25][26][27] which is tightly correlated with the density of AS synapses.…”

Section: Elevated Excitatory Input In Szsupporting

confidence: 72%

“…Some of the control (n = 3) and SZ (n = 5) cases used in this study have also been used in previous studies analyzing synaptic density of the dorsal striatum. [5][6][7][8][9] Coronal blocks of the striatum were immersed in 4% paraformaldehyde and 1% glutaraldehyde in 0.1 M phosphate buffer for at least 1 week (4°C). Striatal tissue was then sectioned at a thickness of 40 µm with a Vibratome into 6 free-floating series.…”

Section: Brain Tissuementioning

confidence: 99%

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Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

McCollum

Walker

Roche

et al. 2015

SCHBUL

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The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico-striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ.Key words: electron microscopy/anatomy/striatum/ synapseThe exact pathophysiology for the origin of schizophrenia (SZ) is unknown, however evidence from decades of research implies that interactions between multiple brain regions and multiple neurotransmitter systems are likely at play. One region that is implicated in SZ pathology is the nucleus accumbens (NAcc). The NAcc integrates signaling from multiple regions of the brain, receiving input from areas including the prefrontal cortex, hippocampus, amygdala, thalamus, and midbrain.1 Importantly, all of these areas have been associated with SZ, making the NAcc a prime region for integrating multiple disrupted areas to provide a comprehensive understanding of SZ pathology.2 Reciprocal connections between the NAcc and substantia nigra/ventral tegmental area (SN/VTA) indicate further importance of this region. Via these connections, the NAcc modulates dopaminergic input to the dorsal striatum, 3 and striatal dopamine (DA) dysfunction is a hallmark characteristic of the disorder.4 Though many studies have implicated the NAcc in SZ, none have been able to describe its circuitry.The purpose of this study was to provide the first ultrastructural analysis in postmortem human NAcc, and examine the neurocircuitry in the NAcc in SZ to establish the role this region may play in the disorder. We used stereological analysis of electron micrographs in postmortem SZ to analyze the organization an...

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Section: Elevated Excitatory Input In Szsupporting

confidence: 72%

Section: Brain Tissuementioning

confidence: 99%

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

McCollum

Walker

Roche

et al. 2015

SCHBUL

Self Cite

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“…Higher numbers of corticostriatal synapses were reported in the anterior caudate in schizophrenia (Roberts et al, 2005b). Alterations may differ between schizophrenia subtypes, with a higher density of excitatory inputs in striatal patches in schizophrenia, but increases in the matrix only in subjects with undifferentiated schizophrenia (Roberts et al, 2008).…”

Section: Snare Protein Levelsmentioning

confidence: 92%

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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“…Postmortem studies have identified structural features in the central nervous system (CNS) that are characteristic for many neurological syndromes and the approach is somewhat successful for certain psychiatric conditions, such as schizophrenia (Roberts et al, 2005;Rowland, 2005). Unfortunately, this analysis is applicable only to deceased individuals and it cannot be used in the initial diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Neuroanatomical phenotypes in the Reeler mouse

et al. 2007

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The reeler mouse (Reln) has been proposed as a neurodevelopmental model for certain neurological and psychiatric conditions and has been studied by qualitative histochemistry and electron microscopy. Using magnetic resonance microscopy (MRM), we have quantitated for the first time the neuromorphology of Reln mice at a resolution of 21.5 m. The neuroanatomical phenotypes of heterozygous and homozygous mutant Reln mice were compared to those of wild type (WT) littermates using morphometry and texture analysis. The cortical, hippocampal, and cerebellar phenotypes of the heterozygous and homozygous mutant Reln mice were confirmed, and new features were revealed. The Reln rl/rl mice possessed a smaller brain, and both Reln rl/+ and Reln rl/rl mice had increased ventricles compared to WT controls. Shape differences were found between WT and Reln rl/rl brains, specifically in cerebellum, olfactory bulbs, dorsomedial frontal and parietal cortex, certain regions of temporal and occipital lobes, as well as in the lateral ventricles and ventral hippocampus. These findings suggest that certain brain regions may be more severely impacted by the Reln mutation than others. Gadolinium-based active-staining demonstrated that layers of the hippocampus were disorganized in Reln rl/rl mice and differences in thickness of these layers were identified between WT and Reln rl/rl mice. The intensity distributions characteristic to the dorsal, middle, and ventral hippocampus were altered in the Reln rl/rl , especially in the ventral hippocampus. These differences were quantified using skewness and modeling the intensity distributions with a Gaussian mixture. Our results suggest that structural features of Reln rl/rl brain most closely phenocopy those of patients with Norman-Roberts lissencephaly.

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Synaptic differences in the postmortem striatum of subjects with schizophrenia: A stereological ultrastructural analysis

Cited by 49 publications

References 121 publications

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

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

Neuroanatomical phenotypes in the Reeler mouse

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