Regulation of Amygdala-Dependent Learning by Brain-Derived Neurotrophic Factor is Mediated by Extracellular Signal-Regulated Kinase and Phosphatidylinositol-3-Kinase

Ou, Li; Gean, Po Wu

doi:10.1038/sj.npp.1300830

Cited by 104 publications

(108 citation statements)

References 42 publications

(42 reference statements)

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“…For example, fear conditioning selectively increases BDNF mRNA in the amygdala, whereas mRNAs of other neurotrophins and trophic factors are unaffected (40). BDNF protein levels and TrkB phosphorylation are also enhanced by fear conditioning (41,42). In our studies, the concentrations of BDNF protein are reduced in the PC7 KO hippocampus and amygdala.…”

Section: Discussionsupporting

confidence: 49%

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

Wetsel

Rodriguiz

Guillemot

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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PC7 belongs to the proprotein convertase family, whose members are implicated in the cleavage of secretory precursors. The in vivo function of PC7 is unknown. Herein, we find that the precursor proBDNF is processed into mature BDNF in COS-1 cells coexpressing proBDNF with either PC7 or Furin. Conversely, the processing of proBDNF into BDNF is markedly reduced in the absence of either Furin or PC7 in mouse primary hepatocytes. In vivo we observe that BDNF and PC7 mRNAs are colocalized in mouse hippocampus and amygdala and that mature BDNF protein levels are reduced in these brain areas in PC7 KO mice but not in the hippocampus of PC1/3 KO mice. Various behavioral tests reveal that in PC7 KO mice spatial memory is intact and plasticity of responding is mildly abnormal. Episodic and emotional memories are severely impaired, but both are rescued with the tyrosine receptor kinase B agonist 7,8-dihydroxyflavone. Altogether, these results support an in vivo role for PC7 in the regulation of certain types of cognitive performance, in part via proBDNF processing. Because polymorphic variants of human PC7 are being characterized, it will be important in future studies to determine their effects on additional physiological and behavioral processes.

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Section: Discussionsupporting

confidence: 49%

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

Wetsel

Rodriguiz

Guillemot

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…PI 3-kinase can directly activate MEK through protein phosphorylation Bondeva et al, 1998), or PDK-1 can directly bind and activate MEK (Sato et al, 2004). In fact, recently Ou and Gean (2006) showed that PI 3-kinase inhibitors attenuate BDNF-induced ERK phosphorylation in rat amygdala, indicating that PI 3-kinase is an upstream regulator of MAP kinase activation. Recently, we observed altered ERK-1/2 signaling at multiple levels, including alterations in activation and expression of ERK-1/2 and B-Raf in postmortem brain of suicide subjects (Dwivedi et al, 2001(Dwivedi et al, , 2006.…”

Section: Discussionmentioning

confidence: 99%

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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Phosphoinositide 3 (PI 3)-kinase is one of the key signaling enzymes that participates in a myriad of physiological functions in brain and is utilized by neurotrophins to mediate neuronal plasticity, cell survival, and inhibition of apoptosis for several neuronal subtypes. Our recent demonstration that expression of neurotrophic factors and activation of the receptor tyrosine kinase B are significantly altered in postmortem brain of suicide subjects led us to examine whether suicide brain is associated with alterations in PI 3-kinase signaling. In prefrontal cortex (PFC), hippocampus, and cerebellum of suicide (n ¼ 28) and nonpsychiatric control (n ¼ 21) subjects we examined catalytic activation of PI 3-kinase, and mRNA and protein levels of regulatory (p85a, p85b) and catalytic (p110a, p110b) subunits of PI 3-kinase. It was observed that the catalytic activity of PI 3-kinase was significantly reduced in PFC and hippocampus of suicide subjects compared with nonpsychiatric control subjects. Competitive PCR analysis revealed significantly reduced mRNA expression of p85b and p110a and increased expression of p85a subunit isoforms in PFC and hippocampus of suicide subjects. Alterations in these catalytic and regulatory subunits were accompanied by changes in their respective protein levels. These changes were not present in cerebellum of suicide subjects. Also, these changes were present in all suicide subjects irrespective of psychiatric diagnosis. Our findings of reduced activation and altered expression of specific PI 3-kinase regulatory and catalytic subunit isoforms demonstrate abnormalities in this signaling pathway in postmortem brain of suicide subjects and suggest possible involvement of aberrant PI 3-kinase signaling in the pathogenic mechanisms of suicide.

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“…The downstream influences of IRS2 can manifest via activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway (44). AKT signaling affects synaptic plasticity, axonal development, amygdala-dependent learning, and behavioral responses to stress (45,46). Additionally, ISLR2 sits on the cell membrane, aids in the guiding of axons, and can facilitate the activation of trk receptors, including NTRK3 (47,48).…”

Section: Resultsmentioning

confidence: 99%

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

Fox

Oler

Shelton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Children with anxious temperament (AT) are particularly sensitive to new social experiences and have increased risk for developing anxiety and depression. The young rhesus monkey is optimal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. In vivo imaging in young monkeys demonstrated that central nucleus of the amygdala (Ce) metabolism is relatively stable across development and predicts AT. Transcriptome-wide gene expression, which reflects combined genetic and environmental influences, was assessed within the Ce. Results support a maladaptive neurodevelopmental hypothesis linking decreased amygdala neuroplasticity to early-life dispositional anxiety. For example, high AT individuals had decreased mRNA expression of neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Moreover, variation in Ce NTRK3 expression was inversely correlated with Ce metabolism and other AT-substrates. These data suggest that altered amygdala neuroplasticity may play a role the early dispositional risk to develop anxiety and depression.positron-emission tomography | microarray | brain imaging T he ability to identify brain mechanisms underlying the risk during childhood for developing anxiety and depression is critical for establishing novel early-life interventions aimed at preventing the chronic and debilitating outcomes associated with these common illnesses. To this end, we have optimized a model of anxious temperament (AT), the conserved at-risk phenotype, in young developing rhesus monkeys (1-4). The rhesus monkey is ideal for studying the origin of human AT because these species share the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning (5-10). Importantly, the rhesus developmental model bridges the critical gap between human psychopathology and rodent models, allowing for translation to humans by using in vivo imaging measures and translation to rodents by using ex vivo molecular methods. Thus, the unique hypotheses that can be generated from the rhesus model are invaluable in guiding both imaging studies in children and mechanistic efforts in rodents.Of particular relevance to the AT rhesus model is the relatively recent evolutionary divergence between rhesus monkeys and humans (25 million years) compared with rodents and humans (70 million years) (5). This evolutionary closeness is reflected in the species' similarities in social and emotional behaviors. These homologies, instantiated in their conserved genetic and neural systems, underlie the ability of both humans and rhesus monkeys to form and maintain the relationships necessary for living in complex social environments. In this regard, the experience of anxiety has evolved in primates to motivate the formation of long-lasting attachment bonds that serve to increase security and group cohesion. The comparable rearing practices shared by these species (e.g., close mother-infant bonding) promote early social/emotional le...

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Regulation of Amygdala-Dependent Learning by Brain-Derived Neurotrophic Factor is Mediated by Extracellular Signal-Regulated Kinase and Phosphatidylinositol-3-Kinase

Cited by 104 publications

References 42 publications

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

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