Vesicular glutamate transporter mRNA expression in the medial temporal lobe in major depressive disorder, bipolar disorder, and schizophrenia

Self Cite

107

We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

Section: Age At Deathmentioning

confidence: 99%

Section: Age At Deathmentioning

confidence: 99%

Section: Prior Medication Exposurementioning

confidence: 99%

See 1 more Smart Citation

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Self Cite

107

“…We have documented its presence in layer V of the cortex . Others indicate that it is also present in layer II, III, and IV pyramidal neurons (Uezato et al, 2009;McCullumsmith and Meador-Woodruff, 2003;Fremeau et al, 2001;Nakamura et al, 2005).…”

Section: Confocal Fluorescence Microscopymentioning

confidence: 99%

Growth Arrest and DNA-Damage-Inducible, Beta (GADD45b)-Mediated DNA Demethylation in Major Psychosis

Gavin

Sharma

Chase

et al. 2011

103

119

Aberrant neocortical DNA methylation has been suggested to be a pathophysiological contributor to psychotic disorders. Recently, a growth arrest and DNA-damage-inducible, beta (GADD45b) protein-coordinated DNA demethylation pathway, utilizing cytidine deaminases and thymidine glycosylases, has been identified in the brain. We measured expression of several members of this pathway in parietal cortical samples from the Stanley Foundation Neuropathology Consortium (SFNC) cohort. We find an increase in GADD45b mRNA and protein in patients with psychosis. In immunohistochemistry experiments using samples from the Harvard Brain Tissue Resource Center, we report an increased number of GADD45b-stained cells in prefrontal cortical layers II, III, and V in psychotic patients. Brain-derived neurotrophic factor IX (BDNF IXabcd) was selected as a readout gene to determine the effects of GADD45b expression and promoter binding. We find that there is less GADD45b binding to the BDNF IXabcd promoter in psychotic subjects. Further, there is reduced BDNF IXabcd mRNA expression, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine at its promoter. On the basis of these results, we conclude that GADD45b may be increased in psychosis compensatory to its inability to access gene promoter regions.

“…This present study is the first to use RNA interference to target the expression of VGLUT1 in a specific brain region in vivo as a novel means of manipulating synaptic glutamate release. Hippocampal expression of VGLUT1 mRNA and protein is decreased in schizophrenia (Eastwood and Harrison, 2005;Sawada et al, 2005;Piyabhan and Reynolds, 2006) and, although striatal deficits have also been reported (Piyabhan and Reynolds, 2006;Nudmamud-Thanoi et al, 2007), cortical changes (which do occur in depression; Gilabert-Juan et al, 2012) are far less robust in schizophrenia (Corti et al, 2007;OniOrisan et al, 2008;Uezato et al, 2009;Eastwood and Harrison, 2010) and appear restricted to specific layers of the prefrontal cortex (Eastwood and Harrison, 2005;Bitanihirwe et al, 2009), whereas the amygdala remains unaffected . The principal finding of the current study is that administration of a VGLUT1-targeting lentiviral shRNA vector into the dorsal hippocampus of Targeting whole-brain VGLUT1 expression using conventional gene knockout strategies results in a 35-41% decrease in transporter levels in heterozygous animals (Tordera et al, 2007;Garcia-Garcia et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

King

Kurian

Qin

et al. 2013

Glutamate is the principle excitatory neurotransmitter in the mammalian brain, and dysregulation of glutamatergic neurotransmission is implicated in the pathophysiology of several psychiatric and neurological diseases. This study utilized novel lentiviral short hairpin RNA (shRNA) vectors to target expression of the vesicular glutamate transporter 1 (VGLUT1) following injection into the dorsal hippocampus of adult mice, as partial reductions in VGLUT1 expression should attenuate glutamatergic signaling and similar reductions have been reported in schizophrenia. The VGLUT1-targeting vector attenuated tonic glutamate release in the dorsal hippocampus without affecting GABA, and selectively impaired novel object discrimination (NOD) and retention (but not acquisition) in the Morris water maze, without influencing contextual fear-motivated learning or causing any adverse locomotor or central immune effects. This pattern of cognitive impairment is consistent with the accumulating evidence for functional differentiation along the dorsoventral axis of the hippocampus, and supports the involvement of dorsal hippocampal glutamatergic neurotransmission in both spatial and nonspatial memory. Future use of this nonpharmacological VGLUT1 knockdown mouse model could improve our understanding of glutamatergic neurobiology and aid assessment of novel therapies for cognitive deficits such as those seen in schizophrenia.