Decreased synaptic and mitochondrial density in the postmortem anterior cingulate cortex in schizophrenia
Introduction
The anterior cingulate cortex (ACC) is part of prefrontal cortex and its neuroanatomy has been well described (DeFelipe et al., 2002, Jones, 1998, Lewis et al., 2002, Peters, 2002). The ACC is composed of distinct anatomical subregions, each with different functional properties (Peterson et al., 1999, Palomero-Gallagher et al., 2008, Vogt et al., 1992). At the microscopic level, each layer of the ACC has characteristic types of neurons, which project to particular targets; each layer is the recipient of inputs from specific regions (DeFelipe et al., 2002, Lewis et al., 2002). Human imaging studies indicate that the dorsal ACC is involved in mediating attention and executive functions, such as task difficulty, remote memory (Koski and Petrides, 2001), conflict (Barch et al., 2001, Kerns et al., 2004), response inhibition and error commission (Braver et al., 2001, Mathalon et al., 2002). The subcallosal ACC is involved in emotional processing (Bush et al., 2000) or internal states (Greicius et al., 2003), the dorsal ACC is involved in cognitive function, and the rostral ACC, located between these two subdivisions, plays an important role in the integration of these functions (Vogt et al., 1992).
The ACC is one of several brain regions that are abnormal in schizophrenia (SZ), as shown in both in vivo imaging and postmortem studies (Fornito et al., 2009). In vivo imaging of people with SZ has shown abnormalities in multiple transmitter systems (Egerton et al., 2012, Kraguljac et al., 2012, Rowland et al., 2013, Théberge et al., 2003), blood flow (Holcomb et al, 2000) and metabolism (Nordahl et al., 1996, Tamminga et al., 1992). Functional impairments in cognitive interference (Heckers et al., 2004), error or conflict monitoring (Alain et al., 2002, Carter et al., 1997, Carter et al., 2001) and response monitoring (Kopp and Rist, 1999, Mathalon et al., 2002) have also been demonstrated.
Postmortem studies have shown multiple defects in the ACC in SZ (Eastwood and Harrison, 2001, Fornito et al., 2009). Neurochemical and molecular changes include altered distribution or modulation of dopamine (Benes et al., 1997), abnormalities in multiple aspects of the glutamate system (Barksdale et al., 2014, Bauer et al., 2008, Bauer et al., 2010, Drummond et al., 2013, Katsel et al., 2011, Oni-Orisan et al., 2008, Woo et al., 2004, Woo et al., 2007) and intracellular signaling abnormalities (Funk et al., 2012, Funk et al., 2014). Mitochondrial pathology has been implicated repeatedly in schizophrenia (Anglin et al., 2012, Manji et al., 2012) and in the ACC, oxidative stress, a result of mitochondrial production of reactive oxygen species, is increased (Wang et al., 2009). Anatomical abnormalities include layer specific alterations in neuronal distribution and density (Benes and Bird, 1987, Brune et al., 2010, Todtenkopf et al., 2005), and increased numbers of glutamatergic (Benes et al., 1987, Benes et al., 1992) and parvalbumin axons (Kalus et al., 1997, Kalus et al., 1999). Of note, previous electron microscopic studies in SZ have shown layer specific abnormalities such as fewer synapses in the ACC (Aganova and Uranova, 1992) and alterations in synapses, mitochondria and oligodendrocytes in other areas of prefrontal cortex (Uranova et al., 2004, Uranova et al., 2007, Uranova et al., 2011).
The purpose of the present study is to compare the synaptic organization and mitochondrial number and morphology in SZ versus normal control postmortem ACC. Several synaptic features were quantified, including morphological features which identify excitatory and inhibitory synapses. This work has been presented in preliminary form (Barksdale et al., 2012a, Barksdale et al., 2012b, Roberts et al., 2013).
Section snippets
Methods
Human brain tissue was obtained with IRB approved protocols from the Maryland Brain Collection and the Alabama Brain Collection. Diagnostic criteria have been described previously (McCollum et al., in press, Roberts et al., 2008). Demographics are presented in Table 1.
Coronal blocks from the dorsal ACC were preserved in fixative and processed for electron microscopy as previously described (McCollum et al., in press). One series of sections was stained for Kluver-Barrera stain as previously
Demographics
Demographics for the groups were similar for age, PMI, sex and race (Table 1).
Synapses
There was no apparent difference in the integrity of the tissue between the NC (Fig. 3) and SZ groups (Fig. 4). As expected, the majority of synapses in both groups were asymmetric axospinous synapses (Figs. 3A,C,D, 4A,D). Asymmetric axodendritic synapses (Figs. 3B, 4A), symmetric axospinous synapses (Figs. 3C, 4B), symmetric axodendritic synapses (Figs. 3E, 4C) were also present in both groups.
In the ACC (layers 3, 5
Discussion
Our main results show reduced overall synaptic density in the ACC in SZ compared to NCs. The synaptic loss was confined to axospinous synapses and was present in layers 3 and 5/6. Both asymmetric and symmetric axospinous synapses were affected, indicating abnormalities in both excitatory and inhibitory transmission, respectively. Overall decreases in synaptic density in the SZ group are consistent with the reduced neuropil hypothesis, which posits fewer cortical synaptic connections (Selemon
Role of funding source
NIMH supported ACL and RCR for time, travel and supplies. NIMH funded JKR for time. The MERIT scholarship funded KAB for time spent on the project.
Contributions
Dr. Roberts designed the experiment, analyzed data and wrote the manuscript. Dr. Barksdale collected data on the electron microscope and analyzed data. Ms. Roche processed the tissue for electron microscopy, did all of the thin sectioning and collected data on the electron microscope. Dr. Lahti designed the experiment and provided input on the meaning and interpretation of the results. All authors contributed to and have approved the final manuscript.
Conflicts of interest
The authors have no conflicts of interest.
Acknowledgments
This research was supported by NIH grant MH081014 (ACL), and a 5K12GM088010-02 MERIT Scholarship (KAB). We thank the staff of the Maryland and Alabama Brain Collections and Racheal McKinney for formatting the references.
References (120)
Inter- and intra-laminar connections of pyramidal cells in the neocortex
Neurosci. Res.
(2005)- et al.
Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia
Schizophr. Res.
(2008) - et al.
Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia
Schizophr. Res.
(2010) - et al.
The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects
Biol. Psychiatry
(2001) - et al.
Magnetic transfer contrast accurately localizes substantia nigra confirmed by histology
Biol. Psychiatry
(2013) - et al.
Cognitive and emotional influences in anterior cingulate cortex
Trends Cogn. Sci.
(2000) - et al.
Mitochondrial trafficking and morphology in healthy and injured neurons
Prog. Neurobiol.
(2006) - et al.
Parvalbumin immunoreactivity reveals layer IV of monkey cerebral cortex as a mosaic of microzones of thalamic afferent terminations
Brain Res.
(1991) - et al.
A light and electron microscopic study of calbindin D-28 k immunoreactive double bouquet cells in the human temporal cortex
Brain Res.
(1995) - et al.
Transmembrane AMPA receptor regulatory protein (TARP) dysregulation in anterior cingulate cortex in schizophrenia
Schizophr. Res.
(2013)
Mitochondria and calcium in health and disease
Cell Calcium
Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins
Brain Res. Bull.
Selective deficit of hippocampal N-acetylaspartate in antipsychotic-naive patients with schizophrenia
Biol. Psychiatry
VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate
Trends Neurosci.
Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia
Schizophr. Res.
Critical period mechanisms in developing visual cortex
Curr. Top. Dev. Biol.
Altered distribution of parvalbumin-immunoreactive local circuit neurons in the anterior cingulate cortex of schizophrenic patients
Psychiatry Res.
Time-related changes in task performance after lesions restricted to the frontal cortex
Neuropsychology
Neurometabolites in schizophrenia and bipolar disorder — a systematic review and metaanalysis
Psychiatry Res.
The dopaminergic innervation of the monkey prefrontal cortex: a tyrosine hydroxylase immunohistochemical study
Brain Res.
The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses
Cell
Antipsychotic treatment induces alterations in dendrite- and spine-associated proteins in dopamine-rich areas of the primate cerebral cortex
Biol. Psychiatry
Synaptic targets of calretinin-containing axon terminals in macaque monkey prefrontal cortex
Neuroscience
N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology
Prog. Neurobiol.
Cytoarchitecture and cortical connections of the anterior cingulate and adjacent somatomotor fields in the rhesus monkey
Brain Res. Bull.
Temporal lobe metabolic differences in medication-free outpatients with schizophrenia via the PET-600
Neuropsychopharmacology
Altered vesicular glutamate transporter expression in the anterior cingulate cortex in schizophrenia
Biol. Psychiatry
An fMRI study of Stroop word-color interference: evidence for cingulate subregions subserving multiple distributed attentional systems
Biol. Psychiatry
Assessments of function and biochemistry of the anterior cingulate cortex in schizophrenia
Biol. Psychiatry
Localization of excitatory amino acid transporters EAAT1 and EAAT2 in human postmortem cortex: a light and electron microscopic study
Neuroscience
The reduced neuropil hypothesis: a circuit based model of schizophrenia
Biol. Psychiatry
Morphometric analysis of synaptic contacts in the anterior limbic cortex in the endogenous psychoses
Neurosci. Behav. Physiol.
Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects
Am. J. Psychiatry
Neurophysiological evidence of error-monitoring deficits in patients with schizophrenia
Cereb. Cortex
The mitochondrial genome and psychiatric illness
Am. J. Med. Genet. B Neuropsychiatr. Genet.
Anterior cingulate cortex and response conflict: effects of response modality and processing domain
Cereb. Cortex
Synaptic and mitochondrial changes in the anterior cingulate cortex in schizophrenia
Neuropsychopharmacology
Synaptic and Mitochondrial Changes in the Postmortem Anterior Cingulate Cortex in Schizophrenia
Program No. 223.11. 2012 Neuroscience Meeting Planner
Synaptic proteins in the postmortem anterior cingulate cortex in schizophrenia: relationship to treatment and treatment response
Neuropsychopharmacology
Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo
NeuroReport
Amygdalocortical circuitry in schizophrenia: from circuits to molecules
Neuropsychopharmacology
An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients
Arch. Gen. Psychiatry
Increased vertical axon numbers in cingulate cortex of schizophrenics
Arch. Gen. Psychiatry
Increased density of glutamate-immunoreactive vertical processes in superficial laminae in cingulate cortex of schizophrenic brain
Cereb. Cortex
Differential distribution of tyrosine hydroxylase fibers on small and large neurons in layer II of anterior cingulate cortex of schizophrenic brain
Synapse
Anterior cingulate cortex pathology in schizophrenia and bipolar disorder
Acta Neuropathol.
Anterior cingulate cortex and response conflict: effects of frequency, inhibition and errors
Cereb. Cortex
Von Economo neuron density in the anterior cingulate cortex is reduced in early onset schizophrenia
Acta Neuropathol.
Comparative evaluation of synaptophysin-based methods for quantification of synapses
J. Neurocytol.
Anterior cingulate gyrus dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during single-trial Stroop task performance
Am. J. Psychiatry
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