Affecting long-term fear memory formation through optical control of Rac1 GTPase and PAK activity in lateral amygdala

Das, Aniruddha; Dines, Monica; Alapin, Jessica M.; Lamprecht, Raphael

doi:10.1038/s41598-017-13674-9

Cited by 21 publications

(27 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also showed that Rac1 inhibition, similar to inhibition of TrkB, rescued anxiety-related velocity of tsc2 vu242/vu242 . In line with our results, Rac1 overactivation was previously shown to inhibit the formation of long-term fear conditioning memory (42). Rac1 is required for commissural axon development specifically in the cortex and controls axon crossing through the AC and corpus callosum in mice (43,44).…”

Section: Discussionsupporting

confidence: 92%

TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex

Kedra

Banasiak

Kisielewska

et al. 2020

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

View full text Add to dashboard Cite

Tuberous Sclerosis Complex (TSC) is a rare genetic disease that manifests with early symptoms, including cortical malformations, childhood epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Cortical malformations arise during embryonic development and have been linked to childhood epilepsy before, but the underlying mechanisms of this relationship remain insufficiently understood. Zebrafish have emerged as a convenient model to study elementary neurodevelopment; however, without in-depth functional analysis, the Tsc2-deficient zebrafish line cannot be used for studies of TANDs or new drug screening. In this study, we found that the lack of Tsc2 in zebrafish resulted in heterotopias and hyperactivation of the mTorC1 pathway in pallial regions, which are homologous to the mammalian cortex. We observed commissural thinning that was responsible for brain dysconnectivity, recapitulating TSC pathology in human patients. The lack of Tsc2 also delayed axonal development and caused aberrant tract fasciculation, corresponding to the abnormal expression of genes involved in axon navigation. The mutants underwent epileptogenesis that resulted in nonmotor seizures and exhibited increased anxiety-like behavior. We further mapped discrete parameters of locomotor activity to epilepsy-like and anxiety-like behaviors, which were rescued by reducing tyrosine receptor kinase B (TrkB) signaling. Moreover, in contrast to treatment with vigabatrin and rapamycin, TrkB inhibition rescued brain dysconnectivity and anxiety-like behavior. These data reveal that commissural thinning results in the aberrant regulation of anxiety, providing a mechanistic link between brain anatomy and human TANDs. Our findings also implicate TrkB signaling in the complex pathology of TSC and reveal a therapeutic target.

show abstract

Section: Discussionsupporting

confidence: 92%

TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex

Kedra

Banasiak

Kisielewska

et al. 2020

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

View full text Add to dashboard Cite

show abstract

“…Several studies have demonstrated a role for Rac1 GTPase in learning and memory formation in the amygdala. Light stimulation of photoactivatable Rac1 (PA-Rac1) during auditory fear conditioning in the LA led to an increase in PAK phosphorylation and to an impairment in long-but not in short-term auditory fear conditioning memory (Das et al, 2017). Inhibiting the downstream effector PAK in LA enhanced longbut not short-term fear conditioning memory.…”

Section: Rac1 Gtpase In Learning and Memory Formationmentioning

confidence: 99%

The Role of Rac GTPase in Dendritic Spine Morphogenesis and Memory

Costa

Dines

Lamprecht

2020

Front. Synaptic Neurosci.

Self Cite

View full text Add to dashboard Cite

The ability to form memories in the brain is needed for daily functions, and its impairment is associated with human mental disorders. Evidence indicates that long-term memory (LTM)-related processes such as its consolidation, extinction and forgetting involve changes of synaptic efficacy produced by alterations in neural transmission and morphology. Modulation of the morphology and number of dendritic spines has been proposed to contribute to changes in neuronal transmission mediating such LTM-related processes. Rac GTPase activity is regulated by synaptic activation and it can affect spine morphology by controlling actin-regulatory proteins. Recent evidence shows that changes in Rac GTPase activity affect memory consolidation, extinction, erasure and forgetting and can affect spine morphology in brain areas that mediate these behaviors. Altered Rac GTPase activity is associated with abnormal spine morphology and brain disorders. By affecting Rac GTPase activity we can further understand the roles of spine morphogenesis in memory. Moreover, manipulation of Rac GTPase activity may serve as a therapeutic tool for the treatment of memory-related brain diseases.

show abstract

“…Rac1 activation on the other hand accelerated memory decay within 24 h. Moreover, expression of active Rac1 produced more lamellipodia-like synapses with a large spine head and overexpression of Rac1-DN led to a reduced spine density, with more long and thin filopodia-like spines. Activation of Rac1 in LA impaired long- but not short-term memory formation (Das et al, 2017 ). In Drosophila, Rac1 also mediates forgetting (Shuai et al, 2010 ; Dong et al, 2016 ).…”

Section: Evidence For a Role For Actin Cytoskeleton And Its Regulatormentioning

confidence: 99%

The Role of Actin Cytoskeleton in Dendritic Spines in the Maintenance of Long-Term Memory

Basu

Lamprecht

2018

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

Evidence indicates that long-term memory formation involves alterations in synaptic efficacy produced by modifications in neural transmission and morphology. However, it is not clear how such alterations induced by learning, that encode memory, are maintained over long period of time to preserve long-term memory. This is especially intriguing as the half-life of most of the proteins that underlie such changes is usually in the range of hours to days and these proteins may change their location over time. In this review we describe studies that indicate the involvement of dendritic spines in memory formation and its maintenance. These studies show that learning leads to changes in the number and morphology of spines. Disruption in spines morphology or manipulations that lead to alteration in their number after consolidation are associated with impairment in memory maintenance. We further ask how changes in dendritic spines morphology, induced by learning and reputed to encode memory, are maintained to preserve long-term memory. We propose a mechanism, based on studies described in the review, whereby the actin cytoskeleton and its regulatory proteins involved in the initial alteration in spine morphology induced by learning are also essential for spine structural stabilization that maintains long-term memory. In this model glutamate receptors and other synaptic receptors activation during learning leads to the creation of new actin cytoskeletal scaffold leading to changes in spines morphology and memory formation. This new actin cytoskeletal scaffold is preserved beyond actin and its regulatory proteins turnover and dynamics by active stabilization of the level and activity of actin regulatory proteins within these memory spines.

show abstract

Affecting long-term fear memory formation through optical control of Rac1 GTPase and PAK activity in lateral amygdala

Cited by 21 publications

References 44 publications

TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex

TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex

The Role of Rac GTPase in Dendritic Spine Morphogenesis and Memory

The Role of Actin Cytoskeleton in Dendritic Spines in the Maintenance of Long-Term Memory

Contact Info

Product

Resources

About