Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia

Pollard, Marie; Varin, Christophe; Hrupka, Brian J.; Pemberton, Darrel J.; Steckler, Thomas; Shaban, Hamdy

doi:10.1016/j.bbr.2011.10.050

Cited by 20 publications

(16 citation statements)

References 47 publications

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“…Hypofunctioning NMDARs within the LA result in memory deficits and have been associated with cognitive deficits found comorbid with several neurological disorders (Schauz and Koch 2000). Indeed, inhibition of NMDA receptors elicits schizophrenic-like symptoms in humans and impairs LTP in the LA (Pollard et al 2012). However, the molecular mechanisms still remain uncertain.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation

et al. 2014

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It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory consolidation. Here we found increases in histone H3 lysine 9 dimethylation (H3K9me2) levels in the LA at 1 h following auditory fear conditioning, which continued to be temporally regulated up to 25 h following behavioral training. Additionally, we demonstrate that inhibiting the H3K9me2 histone lysine methyltransferase G9a (H/KMTs-G9a) in the LA impaired fear memory, while blocking the H3K9me2 histone lysine demethylase LSD1 (H/KDM-LSD1) enhanced fear memory, suggesting that H3K9me2 in the LA can bidirectionally regulate fear memory formation. Furthermore, we show that NMDAR activity differentially regulated the recruitment of H/KMT-G9a, H/KDM-LSD1, and subsequent H3K9me2 levels at a target gene promoter. This was largely regulated by GluN2B-but not GluN2A-containing NMDARs via ERK activation. Moreover, fear memory deficits associated with NMDAR or ERK blockade were successfully rescued through pharmacologically inhibiting LSD1, suggesting that enhancements of H3K9me2 levels within the LA can rescue fear memory impairments that result from hypofunctioning NMDARs or loss of ERK signaling. Together, the present study suggests that histone lysine methylation regulation in the LA via NMDAR-ERK-dependent signaling is involved in fear memory formation.

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Section: Discussionmentioning

confidence: 99%

NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation

et al. 2014

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“…A recent study suggests evidence of impaired LTP in schizophrenia patients with a simultaneous deficit in motor learning (Frantseva et al, 2008). In addition, many schizophrenia animal model studies have also demonstrated an impairment of LTP (Pollard et al, 2012). Of particular interest, a study examining ERBB4 (one of the miR-137 putative target genes), and synaptic potentiation, demonstrated that mice with a full ErbB4 knock-out and mice with a conditional ErbB4 knock-out in only parvalbumin expressing cells exhibit increased hippocampal LTP and lack theta-pulse evoked LTP reversal (Shamir et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Potential Impact of miR-137 and Its Targets in Schizophrenia

2013

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The significant impact of microRNAs (miRNAs) on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. Schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function.

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“…Some early findings had suggested reduced GABAergic signaling in the BLA, but no recent work has focused on the GABAergic system in the BLA (Benes, 2010). Reduction in parvalbumin expression in the BLA has been observed in some animal models of schizophrenia (Romon et al, 2011; Nakamura et al, 2015) but not others (Pollard et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

Loss of Parvalbumin in the Hippocampus of MAM Schizophrenia Model Rats Is Attenuated by Peripubertal Diazepam

Grace

2016

IJNPPY

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Background:Loss of parvalbumin interneurons in the hippocampus is a robust finding in schizophrenia brains. Rats exposed during embryonic day 17 to methylazoxymethanol acetate exhibit characteristics consistent with an animal model of schizophrenia, including decreased parvalbumin interneurons in the ventral hippocampus. We reported previously that peripubertal administration of diazepam prevented the emergence of pathophysiology in adult methylazoxymethanol acetate rats.Methods:We used an unbiased stereological method to examine the impact of peripubertal diazepam treatment on parvalbumin interneuron number in the ventral subiculum, dentate gyrus of the hippocampus and the basolateral amygdala.Results:Methylazoxymethanol acetate rats with peripubertal diazepam showed significantly more parvalbumin interneurons (3355±173 in the ventral subiculum, 1211±76 in the dentate gyrus) than methylazoxymethanol acetate without diazepam (2375±109 and 824±54, respectively). No change was found in the basolateral amygdala.Conclusions:Peripubertal diazepam attenuated the decrease of parvalbumin in the ventral hippocampus of methylazoxymethanol acetate rats.

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Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia

Cited by 20 publications

References 47 publications

NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation

NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation

Potential Impact of miR-137 and Its Targets in Schizophrenia

Loss of Parvalbumin in the Hippocampus of MAM Schizophrenia Model Rats Is Attenuated by Peripubertal Diazepam

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