Hippocampal Hyperexcitability Underlies Enhanced Fear Memories in Tg<i>NTRK3</i>, a Panic Disorder Mouse Model

Santos, Mónica; D’Amico, Davide; Spadoni, Ornella; Amador-Arjona, Alejandro; Stork, Oliver; Dierssen, Mara

doi:10.1523/jneurosci.2161-13.2013

Cited by 38 publications

(34 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the other candidate genes that have been linked to the major psychiatric disorders, nearly all have been found to code for proteins that are involved in the regulation of neuronal excitability [134][135][136][137][138][139][140]. This, taken together with the aforementioned biological, observational, pharmacological, neuropsychiatric, behavioral, medical, psychophysiological, experimental, radiological, and explanatory evidence of the same linkage, is overwhelming evidence that neuronal hyperexcitability is at the root of mental illness.…”

Section: The Gene Researchmentioning

confidence: 99%

The Multi-Circuit Neuronal Hyperexcitability Hypothesis of Psychiatric Disorders

Binder¹

2019

AJCEM

View full text Add to dashboard Cite

After nearly a century of intensive research and clinical investigation, the pathophysiology of psychiatric disorders remains an enigma. Short of a clear understanding of how psychiatric symptoms are produced, the various cognitive, emotional, and behavior patterns that characterize psychiatric disorders continue to be grouped into syndromes and treated accordingly. The weakness of this approach is that the treatment is administered without a clear understanding of what pathological process is being treated. Moreover, the symptoms of most psychiatric disorders are frequently changing and melding into one another. This leads to diagnostic confusion, medication stacking, and poor treatment outcomes, all of which erode patient trust and perpetuate the stigma of mental illness. In this seminal report, a new hypothesis on the pathophysiology of psychiatric disorders will be presented based on multidisciplinary evidence that nearly all psychiatric disorders and their functional comorbidities are rooted in a single, shared, neurophysiological abnormality. The report will then trace that abnormality to its molecular roots and introduce a new paradigm through which the many faces of mental illness can be understood and uniformly treated. The Multi-Circuit Neuronal Hyperexcitability hypothesis of psychiatric disorders posits that an inherent hyperexcitability of the neurological system is at the root of mental illness and provides a precise, functionallyspecific framework that eliminates diagnostic confusion, informs a unified treatment approach, and helps remove the long-held stigma of mental illness. + Itemized comparison showing that the same conditions and chemicals that increase the potential for seizures (upper section) also increase the potential for psychiatric symptoms, and the same conditions and chemicals that decrease the potential for seizures (lower section) also decrease the potential for psychiatric symptoms.

show abstract

Section: The Gene Researchmentioning

confidence: 99%

The Multi-Circuit Neuronal Hyperexcitability Hypothesis of Psychiatric Disorders

Binder¹

2019

AJCEM

View full text Add to dashboard Cite

show abstract

“…In summary, we show that NT3/TrkC homeostasis is altered in the mPFC of TgNTRK3 mice and critically involved in fear extinction deficits in this mouse model of PAND (Dierssen et al, 2006;Santos et al, 2013). The impaired fear extinction is associated with a deficit of NT3 and plasticity in the mPFC-IL brain region, and is rescued by local NT3 infusion.…”

Section: Impaired Fear Extinction Rescue Via Nt3/trkc-erk Pathway D Dmentioning

confidence: 63%

“…In humans, patients affected by PAND are unable to extinguish fear memories (Michael et al, 2007) and present neuroanatomical alterations in prefrontal cortical regions (reviewed in Santos et al, 2015). In our previous work, we have shown deficits in extinction of contextual fear memory in TgNTRK3, a mouse model of PAND (Santos et al, 2013). We here report a deficit in the NT3/TrkC-ERK intracellular signaling in this brain region that seems to causally involved in fear extinction impairment in TgNTRK3 mice and can be recovered by local substitution of NT3 to the mutant mPFC.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that transgenic mice overexpressing the full-length NTRK3 (TgNTRK3 mouse model) recapitulate PAND phenotypes (Dierssen et al, 2006). Importantly, TgNTRK3 mice show fear memories that are resistant to contextual extinction, along with an altered neuronal activation in the hippocampus-amygdala-mPFC fear circuit (Santos et al, 2013). This provides strong face validity, since PAND patients also show exaggerated and pathological fear (Lissek et al, 2005;Lissek et al, 2009) that is resistant to extinction (Michael et al, 2007).…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear

D’Amico

Gener

Lagrán

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

The inability to properly extinguish fear memories constitutes the foundation of several anxiety disorders, including panic disorder. Recent findings show that boosting prefrontal cortex synaptic plasticity potentiates fear extinction, suggesting that therapies that augment synaptic plasticity could prove useful in rescue of fear extinction impairments in this group of disorders. Previously, we reported that mice with selective deregulation of neurotrophic tyrosine kinase receptor, type 3 expression (TgNTRK3) exhibit increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Here we explore the specific role of neurotrophin 3 and its cognate receptor in the medial prefrontal cortex, and its involvement in fear extinction in a pathological context. In this study we combined molecular, behavioral, in vivo pharmacology and ex vivo electrophysiological recordings in TgNTRK3 animals during contextual fear extinction processes. We show that neurotrophin 3 protein levels are increased upon contextual fear extinction in wild-type animals but not in TgNTRK3 mice, which present deficits in infralimbic long-term potentiation. Importantly, infusion of neurotrophin 3 to the medial prefrontal cortex of TgNTRK3 mice rescues contextual fear extinction and ex vivo local application improves medial prefrontal cortex synaptic plasticity. This effect is blocked by inhibition of extracellular signal-regulated kinase phosphorylation through peripheral administration of SL327, suggesting that rescue occurs via this pathway. Our results suggest that stimulating neurotrophin 3-dependent medial prefrontal cortex plasticity could restore contextual fear extinction deficit in pathological fear and could constitute an effective treatment for fear-related disorders.

show abstract

“…Previous studies of additional variants of NTRK3 have shown that this gene is associated with several psychiatric disorders including panic/anxiety disorder (Dierssen et al., 2006; Muinos-Gimeno et al., 2009; Santos et al., 2013), depressive and bipolar disorders (Athanasiu et al., 2011; Feng et al., 2008; Verma et al., 2008), schizophrenia (Otnaess et al., 2009), obsessive–compulsive disorder (Alonso et al., 2008; Muinos-Gimeno et al., 2009), and eating disorders (Mercader et al., 2008). However, the present study was the first to investigate the role that variants of NTRK3 play in influencing one’s susceptibility to substance and non-substance addictive disorders.…”

Section: Discussionmentioning

confidence: 99%

Targeted exome sequencing for the identification of a protective variant against Internet gaming disorder at rs2229910 of neurotrophic tyrosine kinase receptor, type 3 (NTRK3): A pilot study

Kim¹,

Jeong²,

Rhee³

et al. 2016

J Behav Addict

View full text Add to dashboard Cite

Background and aimsInternet gaming disorder (IGD) has gained recognition as a potential new diagnosis in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders, but genetic evidence supporting this disorder remains scarce.MethodsIn this study, targeted exome sequencing was conducted in 30 IGD patients and 30 control subjects with a focus on genes linked to various neurotransmitters associated with substance and non-substance addictions, depression, and attention deficit hyperactivity disorder.Resultsrs2229910 of neurotrophic tyrosine kinase receptor, type 3 (NTRK3) was the only single nucleotide polymorphism (SNP) that exhibited a significantly different minor allele frequency in IGD subjects compared to controls (p = .01932), suggesting that this SNP has a protective effect against IGD (odds ratio = 0.1541). The presence of this potentially protective allele was also associated with less time spent on Internet gaming and lower scores on the Young’s Internet Addiction Test and Korean Internet Addiction Proneness Scale for Adults.ConclusionsThe results of this first targeted exome sequencing study of IGD subjects indicate that rs2229910 of NTRK3 is a genetic variant that is significantly related to IGD. These findings may have significant implications for future research investigating the genetics of IGD and other behavioral addictions.

show abstract

Hippocampal Hyperexcitability Underlies Enhanced Fear Memories in TgNTRK3, a Panic Disorder Mouse Model

Cited by 38 publications

References 48 publications

The Multi-Circuit Neuronal Hyperexcitability Hypothesis of Psychiatric Disorders

The Multi-Circuit Neuronal Hyperexcitability Hypothesis of Psychiatric Disorders

Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear

Targeted exome sequencing for the identification of a protective variant against Internet gaming disorder at rs2229910 of neurotrophic tyrosine kinase receptor, type 3 (NTRK3): A pilot study

Contact Info

Product

Resources

About