BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation

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Rett Syndrome is a neurodevelopmental disorder that arises from mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). MeCP2 has a large number of targets and a wide range of functions, suggesting the hypothesis that functional signaling mechanisms upstream of synaptic and circuit maturation may contribute to our understanding of the disorder and provide insight into potential treatment. Here, we show that insulin-like growth factor-1 (IGF1) levels are reduced in young male Mecp2-null (Mecp2 −/y ) mice, and systemic treatment with recombinant human IGF1 (rhIGF1) improves lifespan, locomotor activity, heart rate, respiration patterns, and social and anxiety behavior. Furthermore, Mecp2-null mice treated with rhIGF1 show increased synaptic and activated signaling pathway proteins, enhanced cortical excitatory synaptic transmission, and restored dendritic spine densities. IGF1 levels are also reduced in older, fully symptomatic heterozygous (Mecp2 −/+ ) female mice, and short-term treatment with rhIGF1 in these animals improves respiratory patterns, reduces anxiety levels, and increases exploratory behavior. In addition, rhIGF1 treatment normalizes abnormally prolonged plasticity in visual cortex circuits of adult Mecp2 −/+ female mice. Our results provide characterization of the phenotypic development of Rett Syndrome in a mouse model at the molecular, circuit, and organismal levels and demonstrate a mechanism-based therapeutic role for rhIGF1 in treating Rett Syndrome. molecular therapeutic | respiration | synaptic function | male mice | female mice R ett Syndrome (RTT) is a devastating, rare neurodevelopmental disorder that primarily afflicts girls. Over 90% of individuals with RTT have sporadic mutations in the X-linked gene coding for methyl-CpG binding protein 2 (MeCP2). Affected girls are initially asymptomatic, but later develop a wide range of symptoms. Mouse models of RTT with deletion of Mecp2 recapitulate many of the key physiological, autonomic, motor, and cognitive aspects of the disorder (1, 2).MeCP2 binds widely across the genome and has complex roles that encompass activating or inhibiting gene transcription, repressing methylation, regulating chromatin remodeling, and altering noncoding RNAs (3). This wide range of functions has led to the proposal that a focus on functional signaling pathways is needed to drive an understanding of RTT and its possible therapeutics (1, 2, 4). Several lines of evidence indicate an arrested brain maturation phenotype in RTT, suggesting that loss of functional MeCP2 leads to immature synapses and circuits in the brain (5). Importantly, mouse models have suggested reversibility of specific symptoms once MeCP2 function is restored (6, 7). One well-documented target of MeCP2 is brain-derived neurotrophic factor (BDNF), which is known to be critical for neuronal and synaptic maturation and is down-regulated in Mecp2 mutant mice and RTT patients (8, 9). BDNF exerts influence on neurons and synapses mainly via the phosphoinositide 3-kinase (PI3K)/Akt pathway ...

Section: Discussionsupporting

confidence: 92%

“…3C). Cortical synaptic PSD95, a postsynaptic protein necessary for glutamate receptor organization and functional responses to plasticity (25,26) (27) (Fig. 3D).…”

Section: Rhigf1 Treatment Curtails Abnormally Prolonged Visual Corticalmentioning

confidence: 99%

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

Castro

Garcia

Kwok

et al. 2014

181

171

“…BDNF belongs to the neurotrophin family and has been shown to play an important role in learning and memory (34,35). BDNF signaling through its primary receptor TrkB has also been shown to play a significant role in downstream effects underlying learning (36)(37)(38)(39)(40). Previous data from our laboratory have shown increased BDNF transcription and translation in the OB following olfactory fear conditioning (41).…”

Section: Discussionmentioning

confidence: 95%

Extinction reverses olfactory fear-conditioned increases in neuron number and glomerular size

Morrison

Dias

Ressler

2015

Although much work has investigated the contribution of brain regions such as the amygdala, hippocampus, and prefrontal cortex to the processing of fear learning and memory, fewer studies have examined the role of sensory systems, in particular the olfactory system, in the detection and perception of cues involved in learning and memory. The primary sensory receptive field maps of the olfactory system are exquisitely organized and respond dynamically to cues in the environment, remaining plastic from development through adulthood. We have previously demonstrated that olfactory fear conditioning leads to increased odorant-specific receptor representation in the main olfactory epithelium and in glomeruli within the olfactory bulb. We now demonstrate that olfactory extinction training specific to the conditioned odor stimulus reverses the conditioning-associated freezing behavior and odor learning-induced structural changes in the olfactory epithelium and olfactory bulb in an odorant ligand-specific manner. These data suggest that learninginduced freezing behavior, structural alterations, and enhanced neural sensory representation can be reversed in adult mice following extinction training.fear extinction | olfaction | neural plasticity I ncreasing evidence suggests that the cellular, neuroanatomical, and receptive field organizations of vertebrate sensory systems are continually reshaped throughout adulthood by cues from the external environment. Activity-dependent changes are known to occur both during critical periods of development and also in the adult brain, allowing the animal to optimally perform behaviors based on the demands of the surrounding environment. Postmitotic organizational changes, along with activity-dependent plasticity, have been largely implicated in shaping sensory circuits from development through adulthood (1-4). In particular, the olfactory sensory system of adult mice exhibits functional and neuroanatomical learning-dependent changes following olfactory fear conditioning in adulthood (5-7). The M71-LacZ transgenic mouse line expresses LacZ under the M71 odorant receptor (OR) promoter (encoded by the olfactory receptor 151 gene, Olfr151) (8) in the M71 OR-expressing, acetophenone-responsive population of olfactory sensory neurons (OSNs). Using this line, we previously demonstrated an increased number of M71-expressing OSNs in the main olfactory epithelium (MOE) of adult mice following olfactory fear conditioning to acetophenone (5, 7), an odorant that activates the M71/M72 ORs (9, 10). This increase in receptor-specific OSNs within the MOE was directly correlated with an increase in the area of M71+ axons innervating the M71 glomeruli within the olfactory bulbs (OBs). Behaviorally, these olfactory fear-conditioned mice also exhibited enhanced fear-potentiated startle (FPS) and freezing specific to the conditioned odor stimulus. Notably such changes were never seen with equivalent odorant exposure alone but only when the odorant was paired with an aversive or appetitive cue (5, 7), sugges...

“…(1-3)IGF-1 treatment phosphorylates the IGF-1 receptor and also leads to activation of the MAPK cascade (data not shown), another signaling pathway that is stimulated by BDNF and is involved in synaptic stabilization (17,46). Although IGF-1 treatment does not increase BDNF levels in MeCP2 mutant mice (as measured with ELISA on whole brain extracts of MeCP2 -/y adult mice, data not shown), it is plausible that it would partially mimic BDNF action by stimulating common downstream signals (23,46). IGF-1 infusion into the brain up-regulates intracortical inhibition and the expression of extracellular matrix molecules (43), which are additional mechanisms that promote the maturation and stabilization of cortical circuits (47).…”

Section: Discussionmentioning

confidence: 99%

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Tropea

Giacometti

Wilson

et al. 2009

517

442