Synaptic Proteome Alterations in the Primary Auditory Cortex of Individuals With Schizophrenia

MacDonald, Matthew L.; Garver, Megan; Newman, J. C.; Sun, Zhe; Kannarkat, Joseph T; Salisbury, Ryan; Glausier, Jill R.; Ding, Ying; Lewis, David A.; Yates, Nathan A.; Sweet, Robert A.

doi:10.1001/jamapsychiatry.2019.2974

Cited by 38 publications

(43 citation statements)

References 71 publications

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“…Using dualantigen immunofluorescence, we also demonstrate co-localization of SR with the PSD marker, PSD-95 in CA1 ( Fig 2D). Finally, mass spectrometry confirmed the presence of SR in synaptosomes (MacDonald et al, 2019) prepared from human hippocampus, along with other well-known pre-and post-synaptic markers (Fig 2E,Extended Data Since we detected the enzyme SR in dendrites and spines, we next examined whether the NMDAR coagonist D-serine is also localized to these compartments. Using immuno-EM and a D-serine immunostaining protocol that we previously validated using SRKO mice (Balu et al, 2014), we observed high numbers of nanogold particles in CA1 s.r.…”

Section: Postsynaptic Localization Of Serine Racemase and D-serinementioning

confidence: 53%

Postsynaptic serine racemase regulates NMDA receptor function

Wong

Folorunso

Barragan

et al. 2020

Preprint

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D-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic D-serine remains limited. Though early studies suggested D-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and D-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons, as well as the presence of SR in human hippocampal synaptosomes. In addition, using a single-neuron genetic approach in SR conditional knockout mice, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at one month of age. Interestingly, there was a restoration of LTP by two months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of D-serine action.

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Section: Postsynaptic Localization Of Serine Racemase and D-serinementioning

confidence: 53%

Postsynaptic serine racemase regulates NMDA receptor function

Wong

Folorunso

Barragan

et al. 2020

Preprint

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“…The majority of these studies found no statistically significant effects of either HAL or OLZ on SYN protein levels in the rat hippocampus and frontal cortex 23,[38][39][40] ; one study reported increased SYN levels in cortical lysates upon chronic administration of OLZ, however this study did not use clinically comparable dosing 41 . Supporting the majority of the rat studies, exposure of rhesus monkeys to clinically-comparable levels of HAL for >1 year found no change in SYN, either at DNA or protein levels, in cortical areas relevant to schizophrenia 42,43 . The effect of APD on postsynaptic marker expression has mostly been investigated at the mRNA level, with Homer1a and PSD-95 as the most commonly reported markers.…”

Section: Summary and Interpretation Of Resultsmentioning

confidence: 75%

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

Halff

Cotel

Natesan

et al. 2020

Preprint

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The pathophysiology of the majority of neuropsychiatric disorders, including schizophrenia and mood disorders, involves synaptic dysfunction and/or loss, manifesting as lower levels of several presynaptic and postsynaptic marker proteins. Whether chronic exposure to antipsychotic drugs may contribute to this pattern of synaptic loss remains controversial. In contrast, the mood stabiliser lithium has shown to exhibit neurotrophic actions and is thought to enhance synapse formation. Whilst these data are not unequivocal, they suggest that antipsychotic drugs and lithium have contrasting effects on synapse density. We therefore investigated the effect of chronic exposure to lithium and to two different antipsychotics, haloperidol and olanzapine, on presynaptic Synaptic Vesicle glycoprotein 2A (SV2A) and postsynaptic Neuroligin (NLGN) clusters in the rat frontal cortex. Chronic exposure (28 days) to haloperidol (0.5 mg/kg/d) or olanzapine (7.5 mg/kg/d) had no effect on either SV2A or NLGN clusters and no overall effect on synaptic clusters. In contrast, chronic lithium exposure (2 mmol/L eq./d) significantly increased NLGN cluster density as compared to vehicle, but did not affect either SV2A or total synaptic clusters. These data are consistent with and extend our prior work, confirming no effect of either antipsychotics or lithium on SV2A clustering, but suggest contrasting effects of these drugs on the post-synapse. Although caution needs to be exerted when extrapolating results from animals to patients, these data provide clarity with regard to the effect of antipsychotics and lithium on synaptic markers, thus facilitating discrimination of drug from illness effects in human studies of synaptic pathology in psychiatric disorders.

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“…Also increased protein insolubility was found in STG and frontal cortex in schizophrenia [ 29 ]. Recently, reductions in synaptosome levels of post-synaptic excitatory proteins were reported in primary auditory cortex of schizophrenia [ 30 ], consistent with synaptic glutamatergic hypofunction. Hence, this literature converges with our findings to support that left STG abnormalities with early hypoglutamatergic dysfunction may be a trait characteristic of schizophrenia.…”

Section: Discussionmentioning

confidence: 91%

Glutamatergic hypo-function in the left superior and middle temporal gyri in early schizophrenia: a data-driven three-dimensional proton spectroscopic imaging study

Bustillo

Upston

Mayer

et al. 2020

Neuropsychopharmacol.

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Proton magnetic resonance spectroscopy ( 1 H-MRS) studies have examined glutamatergic abnormalities in schizophrenia, mostly in single voxels. Though the critical brain nodes remain unknown, schizophrenia involves networks with broad abnormalities. Hence, glutamine plus glutamate (Glx) and other metabolites were examined with whole-brain 1 H-MRS, in early schizophrenia. Three dimensional 1 H-MRS was acquired in young schizophrenia subjects ( N = 36, 19 antipsychotic-naïve and 17 antipsychotic-treated) and healthy controls (HC, N = 29). Glx (as well as N -acetylaspartate, choline, myo-inositol and creatine) group contrasts from all individual voxels that met spectral quality, were analyzed in common brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05). Schizophrenia subjects had lower Glx in the left superior (STG) and middle temporal gyri (16 voxels, CCLAV = 0.04) and increased creatine in two clusters involving left temporal, parietal and occipital regions (32, and 18 voxels, CCLAV = 0.02 and 0.04, respectively). Antipsychotic-treated and naïve patients (vs HC) had similar Glx reductions (8/16 vs 10/16 voxels respectively, but CCLAV’s > 0.05). However, creatine was higher in antipsychotic-treated vs HC’s in a larger left hemisphere cluster (100 voxels, CCLAV = 0.01). Also in treated patients, choline was increased in left middle frontal gyrus (18 voxels, CCLAV = 0.04). Finally in antipsychotic-naive patients, NAA was reduced in right frontal gyri (19 voxels, CCLAV = 0.05) and myo-inositol was reduced in the left cerebellum (34 voxels, CCLAV = 0.02). We conclude that data-driven spectroscopic brain examination supports that reductions in Glx in the left STG may be critical to the pathophysiology of schizophrenia. Postmortem and neuromodulation schizophrenia studies focusing on left STG, may provide critical mechanistic and therapeutic advancements, respectively.

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Synaptic Proteome Alterations in the Primary Auditory Cortex of Individuals With Schizophrenia

Cited by 38 publications

References 71 publications

Postsynaptic serine racemase regulates NMDA receptor function

Postsynaptic serine racemase regulates NMDA receptor function

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

Glutamatergic hypo-function in the left superior and middle temporal gyri in early schizophrenia: a data-driven three-dimensional proton spectroscopic imaging study

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