Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation

Hill, Joanne M.; Hardy, Nicholas F.; Jimenez, Dennisse V.; Maynard, Kristen R.; Kardian, Alisha; Pollock, C J; Schloesser, Robert J.; Martinowich, Keri

doi:10.1038/tp.2016.153

Cited by 50 publications

(47 citation statements)

References 83 publications

(156 reference statements)

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“…While we have identified several electrophysiological alterations in BDNF +/− mice, including aberrant neural oscillations and also marked reductions in several components of the ERP, it is unclear what the consequences of each of these might be. The most notable disturbance to the ERP was the reduced magnitude of C4, a negative deflection on the EEG occurring ~40 ms after the acoustic stimuli, an observation similar to that observed in another genetic mouse model exhibiting reduced BDNF expression (Hill et al ., ). This may be analogous to the N100 component observed in humans and reflects activity in primary auditory and associative cortex (Gallinat et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…Despite the large literature on BDNF abnormalities in schizophrenia, little has been carried out to relate this growth factor to electrophysiological responses. One pertinent study deleted exon IV of the BDNF promoter, leading to reduced BDNF expression, and identified reduced power and coherence of beta and gamma oscillations following auditory stimulation (Hill et al, 2016). Also, hippocampal deletion of TrkBthe primary receptor of BDNFfrom parvalbumin-positive (PV+ve) GABAergic interneurons significantly decreases the power of gamma oscillations in a slice preparation (Zheng et al, 2011), while BDNF also acutely reduces excitability of hippocampal PV+ve interneurons (Nieto-Gonzalez & Jensen, 2013), an effect which might be expected to result in network disinhibition and increased oscillations.…”

Section: Introductionmentioning

confidence: 99%

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Brain‐derived neurotrophic factor haploinsufficiency impairs high‐frequency cortical oscillations in mice

Jones

Hudson

Foreman

et al. 2017

Eur J of Neuroscience

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Schizophrenia is a complex psychiatric disorder with a heterogeneous aetiology involving genetic and environmental factors. Deficiencies in both brain-derived neurotrophic factor (BDNF) and NMDA receptor function have been implicated in the disorder and may play causal and synergistic roles. Perturbations in the regulation of electrophysiological signals, including high-frequency (γ: 30-80 Hz and β: 20-30 Hz) neuronal oscillations, are also associated with the disorder. This study investigated the influence of BDNF deficiency and NMDA receptor hypofunction on electrophysiological responses to brief acoustic stimuli. Adult BDNF heterozygote (BDNF ) and wild-type littermate C57Bl/6J mice were surgically implanted with EEG recording electrodes. All mice underwent EEG recording sessions to measure ongoing and auditory-evoked electrophysiological responses following treatment with MK-801 (0.3 mg/kg ip) or vehicle. Western blotting on post-mortem cortical tissue assessed parvalbumin and GAD67 expression - markers of interneurons which are involved in the generation of gamma oscillations. Compared with wild-type controls, BDNF mice exhibited markedly dampened electrophysiological responses to auditory stimuli, including reductions in the amplitude of multiple components of the event-related potential and auditory-evoked oscillations, as well as reduced ongoing cortical gamma oscillations. MK-801 elevated ongoing gamma power but suppressed evoked gamma power, and this was observed equally across genotypes. BDNF mice also displayed reductions in parvalbumin, but not GAD67 expression. We conclude that reduced BDNF expression leads to impairments in the generation of high-frequency neural oscillations, but this is not synergistic with NMDA receptor hypofunction. Reduced parvalbumin expression associated with BDNF haploinsufficiency may provide a molecular explanation for these electrophysiological deficits.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Brain‐derived neurotrophic factor haploinsufficiency impairs high‐frequency cortical oscillations in mice

Jones

Hudson

Foreman

et al. 2017

Eur J of Neuroscience

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“…We focused on transcripts derived from these promoters as they represent the majority of Bdnf mRNAs in the brain (Aid et al 2007; Pruunsild et al 2007) and disruption of BDNF from these promoters leads to distinct changes in hippocampal BDNF protein expression and unique neurobehavioral deficits (Hill et al 2016; Maynard et al 2016). We also analyzed dendritic spine density and morphology on CA1 apical and basal dendrite branches in Bdnf-e6 mutants.…”

Section: Introductionmentioning

confidence: 99%

Bdnf mRNA splice variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus

et al. 2017

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Brain-derived neurotrophic factor (BDNF) is an activity-dependent neurotrophin critical for neuronal plasticity in the hippocampus. BDNF is encoded by multiple transcripts with alternative 5′ untranslated regions (5′UTRS) that display activity-induced targeting to distinct subcellular compartments. While individual Bdnf 5′UTR transcripts influence dendrite morphology in cultured hippocampal neurons, it is unknown whether Bdnf splice variants impact dendrite arborization in functional classes of neurons in the intact hippocampus. Moreover, the contribution of Bdnf 5′UTR splice variants to dendritic spine density and shape has not been explored. We analyzed the structure of CA1 and CA3 dendrite arbors in transgenic mice lacking BDNF production from exon (Ex) 1, 2, 4, or 6 splice variants (Bdnf-e1, -e2, -e4, and -e6 −/− mice) and found that loss of BDNF from individual Bdnf mRNA variants differentially impacts the complexity of apical and basal arbors in vivo. Consistent with subcellular localization studies, Bdnf Ex2 and Ex6 transcripts significantly contributed to dendrite morphology in both CA1 and CA3 neurons. While Bdnf-e2 −/− mice showed increased branching proximal to the soma in CA1 and CA3 apical arbors, Bdnf-e6 −/− mice showed decreased apical and basal dendrite complexity. Analysis of spine morphology on Bdnf-e6 −/− CA1 dendrites revealed changes in the percentage of differently sized spines on apical, but not basal, branches. These results provide further evidence that Bdnf splice variants generate a spatial code that mediates the local actions of BDNF in distinct dendritic compartments on structural and functional plasticity.

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“…This appears to be due to increased DNA methylation of Bdnf exon IV and a concomitant decrease in mRNA expression within the medial prefrontal cortex [113]. Similarly, Bdnf-e4 mice, in which the activity-dependent promoter in exon IV is disrupted, have impaired fear extinction and decreased hippocampal-medial PFC theta phase synchrony during extinction learning [126]. Conversely, exposure during adolescence to predictable chronic mild stress facilitates fear extinction and this appears to be related to increased BDNF/ERK1/2 signaling in infralimbic cortex in adulthood resulting from decreased DNA methylation of the Bdnf gene at exons IV and VI.…”

Section: Bdnf and Fearmentioning

confidence: 98%

Thermoregulatory Fear of Harm Mood Disorder: In Depth Exploration of a Unique Juvenile-Onset Phenotype That Provides a Parsimonious Clinical Description of Certain Youths with Highly Comorbid Treatment Refractory Psychiatric Disorders

Papolos¹,

Mattis²,

Lachman³

et al. 2019

J Psychiatry Brain Sci

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Among aggressive youths with severe mood lability who frequently fail to benefit from mood stabilizers and antipsychotics there is a discrete subtype called 'Thermoregulatory Fear of Harm Mood Disorder' (FOH). This disorder is characterized by an underlying thermoregulatory deficit, a specific prodromal sequence and a unique constellation of symptoms.The underlying problem appears to be a deficit in thermoregulation resulting in excessive heat that manifests as thermal discomfort in neutral ambient temperatures and moderate to extreme cold tolerance, and produces REM sleep-related problems and parasomnias, such as night-terrors and hypnogogic hallucinations. Clinically, FOH is associated with the advent in childhood of frequent, recurrent, vivid nightmares with themes of pursuit and abandonment. The apparent psychological sequelae of exposure to this frightening imagery is fear sensitization and auto-traumatization. A developmental sequence of fear based defensive behaviors arises and includes obsessive bedtime rituals, fear of the dark, separation anxiety, contamination fears, hypervigilance, perfectionism, misperception of neutral stimuli as threatening, as well as reactive aggression in response to limit setting and perceived threat or loss. Ketamine, chosen as a potential treatment because of its effectiveness in reducing fear sensitization and dose-dependent lowering of body temperature in preclinical studies, has been associated with sustained Journal of Psychiatry and Brain Science 2 of 43 J Psychiatry Brain Sci. 2019;4:e190004. https://doi.org/10.20900/jpbs.20190004 improvement in otherwise refractory youths. We present a detailed description of this heritable disorder, link its clinical features to a potential disturbance in brain derived neurotropic factor (BDNF) and orexin, and indicate how ketamine rapidly affects BDNF through multiple mechanisms, to produce a dramatic beneficial response in youths with this disorder.

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Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation

Cited by 50 publications

References 83 publications

Brain‐derived neurotrophic factor haploinsufficiency impairs high‐frequency cortical oscillations in mice

Brain‐derived neurotrophic factor haploinsufficiency impairs high‐frequency cortical oscillations in mice

Bdnf mRNA splice variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus

Thermoregulatory Fear of Harm Mood Disorder: In Depth Exploration of a Unique Juvenile-Onset Phenotype That Provides a Parsimonious Clinical Description of Certain Youths with Highly Comorbid Treatment Refractory Psychiatric Disorders

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