Publications by authors named "Michelle D Amaral"

16 Publications

  • Page 1 of 1

Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities.

Genet Med 2021 Mar 28;23(3):534-542. Epub 2020 Oct 28.

Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

Purpose: Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described.

Methods: We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants.

Results: We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein.

Conclusion: Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.
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http://dx.doi.org/10.1038/s41436-020-01016-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935712PMC
March 2021

Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases.

Am J Hum Genet 2020 05 23;106(5):632-645. Epub 2020 Apr 23.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, United States. Electronic address:

We conducted genome sequencing to search for rare variation contributing to early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 435 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than one in 10,000 or private), computational prediction of deleteriousness (CADD) (10 or 15 thresholds), and molecular function (protein loss-of-function [LoF] only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Replication analysis was conducted on 16,434 independent cases and 15,587 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p = 4.6 × 10, genome-wide corrected p = 0.0026). Most of these variants were canonical LoF or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of Alzheimer's disease (AD) and FTD (replication only p = 0.0029). The combined analysis odds ratio was 2.3 (95% confidence interval [CI] 1.6-3.4) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 3.7 (95% CI 1.7-9.4). For LoF variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.1 (95% CI 1.9-5.2). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.
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http://dx.doi.org/10.1016/j.ajhg.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212268PMC
May 2020

Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles.

Cold Spring Harb Mol Case Stud 2019 12 13;5(6). Epub 2019 Dec 13.

Alzheimer's Disease Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41-76). Fifty percent of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics and Genomics standards, including variants in , , , and Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2-5) in , , , , , and All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two ε4 alleles. One patient had two ε4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) in , , , , , , , , , , , and , also often along with other variants. In summary, genome sequencing for early-onset dementia frequently identified multiple established or possible contributory alleles. These observations add support for an oligogenic model for early-onset dementia.
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http://dx.doi.org/10.1101/mcs.a003491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913143PMC
December 2019

Child Neurology: Spastic paraparesis and dystonia with a novel mutation.

Neurology 2019 09;93(11):510-514

From the Departments of Neurology (M.D., D.G.S.) and Genetics (L.M., B.R.K.) and Division of Pediatric Neurology, Department of Pediatrics (S.R.), University of Alabama at Birmingham; and HudsonAlpha Institute for Biotechnology (G.M.C., M.D.A.), Huntsville, AL.

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http://dx.doi.org/10.1212/WNL.0000000000008089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746208PMC
September 2019

Genomic sequencing identifies secondary findings in a cohort of parent study participants.

Genet Med 2018 12 12;20(12):1635-1643. Epub 2018 Apr 12.

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.

Purpose: Clinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.

Methods: Exome/genome sequencing and analysis of 789 "unaffected" parents was performed.

Results: Pathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the American College of Medical Genetics and Genomics. These 25 individuals self-reported either relevant clinical diagnoses (5); relevant family history or symptoms (13); or no relevant family history, symptoms, or clinical diagnoses (7). A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as mate pairs (n = 365) to identify cases in which both parents were carriers for the same recessive disease, yielding three such cases (0.8%), two of which had children with the relevant recessive disease. Four participants had two findings (one carrier and one noncarrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings.

Conclusion: We provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design and implementation of research and clinical sequencing efforts to identify such findings.
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http://dx.doi.org/10.1038/gim.2018.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185813PMC
December 2018

Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.

Hum Mol Genet 2018 07;27(14):2454-2465

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder.
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http://dx.doi.org/10.1093/hmg/ddy146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030957PMC
July 2018

Genomic diagnosis for children with intellectual disability and/or developmental delay.

Genome Med 2017 05 30;9(1):43. Epub 2017 May 30.

HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA.

Background: Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.

Methods: Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected).

Results: Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP.

Conclusions: Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.
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http://dx.doi.org/10.1186/s13073-017-0433-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448144PMC
May 2017

Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.

Am J Hum Genet 2016 06 12;98(6):1067-1076. Epub 2016 May 12.

Baylor College of Medicine, Houston, TX 77030, USA.

Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908185PMC
June 2016

Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca(2+) -permeable TRPC6 channels.

Hippocampus 2013 Jan 20;23(1):40-52. Epub 2012 Jul 20.

Department of Neurobiology, Civitan International Research Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

The standardized extract of the St. John's wort plant (Hypericum perforatum) is commonly used to treat mild to moderate depression. Its active constituent is hyperforin, a phloroglucinol derivative that reduces the reuptake of serotonin and norepinephrine by increasing intracellular Na(+) concentration through the activation of nonselective cationic TRPC6 channels. TRPC6 channels are also Ca(2+) -permeable, resulting in intracellular Ca(2+) elevations. Indeed, hyperforin activates TRPC6-mediated currents and Ca(2+) transients in rat PC12 cells, which induce their differentiation, mimicking the neurotrophic effect of nerve growth factor. Here, we show that hyperforin modulates dendritic spine morphology in CA1 and CA3 pyramidal neurons of hippocampal slice cultures through the activation of TRPC6 channels. Hyperforin also evoked intracellular Ca(2+) transients and depolarizing inward currents sensitive to the TRPC channel blocker La(3+) , thus resembling the actions of the neurotrophin brain-derived neurotrophic factor (BDNF) in hippocampal pyramidal neurons. These results suggest that the antidepressant actions of St. John's wort are mediated by a mechanism similar to that engaged by BDNF.
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http://dx.doi.org/10.1002/hipo.22052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538039PMC
January 2013

Intracellular Ca2+ stores and Ca2+ influx are both required for BDNF to rapidly increase quantal vesicular transmitter release.

Neural Plast 2012 3;2012:203536. Epub 2012 Jul 3.

Department of Neurobiology, Civitan International Research Center, The University of Alabama at Birmingham, SHEL-1002, 1825 University Boulevard, Birmingham, AL 35294-2182, USA.

Brain-derived neurotrophic factor (BDNF) is well known as a survival factor during brain development as well as a regulator of adult synaptic plasticity. One potential mechanism to initiate BDNF actions is through its modulation of quantal presynaptic transmitter release. In response to local BDNF application to CA1 pyramidal neurons, the frequency of miniature excitatory postsynaptic currents (mEPSC) increased significantly within 30 seconds; mEPSC amplitude and kinetics were unchanged. This effect was mediated via TrkB receptor activation and required both full intracellular Ca(2+) stores as well as extracellular Ca(2+). Consistent with a role of Ca(2+)-permeable plasma membrane channels of the TRPC family, the inhibitor SKF96365 prevented the BDNF-induced increase in mEPSC frequency. Furthermore, labeling presynaptic terminals with amphipathic styryl dyes and then monitoring their post-BDNF destaining in slice cultures by multiphoton excitation microscopy revealed that the increase in frequency of mEPSCs reflects vesicular fusion events. Indeed, BDNF application to CA3-CA1 synapses in TTX rapidly enhanced FM1-43 or FM2-10 destaining with a time course that paralleled the phase of increased mEPSC frequency. We conclude that BDNF increases mEPSC frequency by boosting vesicular fusion through a presynaptic, Ca(2+)-dependent mechanism involving TrkB receptors, Ca(2+) stores, and TRPC channels.
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http://dx.doi.org/10.1155/2012/203536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397209PMC
November 2012

Activity-dependent release of endogenous BDNF from mossy fibers evokes a TRPC3 current and Ca2+ elevations in CA3 pyramidal neurons.

J Neurophysiol 2010 May 10;103(5):2846-56. Epub 2010 Mar 10.

Department of Neurobiology, Evelyn McKnight Brain Institute, Civitan International Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.

Multiple studies have demonstrated that brain-derived neurotrophic factor (BDNF) is a potent modulator of neuronal structure and function in the hippocampus. However, the majority of studies to date have relied on the application of recombinant BDNF. We herein report that endogenous BDNF, released via theta burst stimulation of mossy fibers (MF), elicits a slowly developing cationic current and intracellular Ca(2+) elevations in CA3 pyramidal neurons with the same pharmacological profile of the transient receptor potential canonical 3 (TRPC3)-mediated I(BDNF) activated in CA1 neurons by brief localized applications of recombinant BDNF. Indeed, sensitivity to both the extracellular BDNF scavenger tropomyosin-related kinase B (TrkB)-IgG and small hairpin interference RNA-mediated TRPC3 channel knockdown confirms the identity of this conductance as such, henceforth-denoted MF-I(BDNF). Consistent with such activity-dependent release of BDNF, these MF-I(BDNF) responses were insensitive to manipulations of extracellular Zn(2+) concentration. Brief theta burst stimulation of MFs induced a long-lasting depression in the amplitude of excitatory postsynaptic currents (EPSCs) mediated by both AMPA and N-methyl-d-aspartate (NMDA) receptors without changes in the NMDA receptor/AMPA receptor ratio, suggesting a reduction in neurotransmitter release. This depression of NMDAR-mediated EPSCs required activity-dependent release of endogenous BDNF from MFs and activation of Trk receptors, as it was sensitive to the extracellular BDNF scavenger TrkB-IgG and the tyrosine kinase inhibitor k-252b. These results uncovered the most immediate response to endogenously released--native--BDNF in hippocampal neurons and lend further credence to the relevance of BDNF signaling for synaptic function in the hippocampus.
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http://dx.doi.org/10.1152/jn.01140.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867575PMC
May 2010

The dynamics of excitatory synapse formation on dendritic spines.

Cellscience 2009 Apr;5(4):19-25

Department of Neurobiology, McKnight Brain Institute, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Dendritic spines, the postsynaptic compartments of most functional excitatory synapses in the Central Nervous System (CNS), are highly dynamic structures, having the ability to grow, change shape, or retract in response to varying levels of neuronal activity. This dynamic nature of spines allows modifications in brain circuitry and connectivity, thus participating in fundamental processes such as learning, recall, and emotional behaviors. Although many studies have characterized the precise molecular identities and signaling pathways by which spines initially form, little is known about the actual time course over which they mature into functional postsynaptic compartments of excitatory synapses. A recent publication in Neuron addresses this issue by studying dendritic spine growth in response to multiphoton glutamate uncaging, simultaneously monitoring the amplitudes of the resultant postsynaptic currents and intracellular Ca(2+) transients within individual spines in CA1 pyramidal neurons in organotypic cultures of postnatal hippocampal slices. The authors describe that dendritic spines are able to respond to glutamate shortly after their formation, leading to the conclusion that spine growth and glutamate receptor recruitment are closely coupled temporally. AMPA receptor-mediated currents exhibited similar amplitudes in newly formed spines compared with older, more mature spines when their volume was taken into account. In addition, NMDA receptor-mediated currents also appeared early after spine formation, although the amount of Ca(2+) entry through these receptors was significantly lower in newly formed spines compared to older, mature spines. Within just a couple of hours, these newly formed spines were contacted by presynaptic terminals, thus acquiring a morphological appearance indistinguishable from already existing mature excitatory synapses.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805008PMC
April 2009

BDNF induces calcium elevations associated with IBDNF, a nonselective cationic current mediated by TRPC channels.

J Neurophysiol 2007 Oct 15;98(4):2476-82. Epub 2007 Aug 15.

Department of Neurobiology, Civitan International Research Center and McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.

Brain-derived neurotrophic factor (BDNF) has potent actions on hippocampal neurons, but the mechanisms that initiate its effects are poorly understood. We report here that localized BDNF application to apical dendrites of CA1 pyramidal neurons evoked transient elevations in intracellular Ca(2+) concentration, which are independent of membrane depolarization and activation of N-methyl-d-aspartate receptors (NMDAR). These Ca(2+) signals were always associated with I(BDNF), a slow and sustained nonselective cationic current mediated by transient receptor potential canonical (TRPC3) channels. BDNF-induced Ca(2+) elevations required functional Trk and inositol-tris-phosphate (IP(3)) receptors, full intracellular Ca(2+) stores as well as extracellular Ca(2+), suggesting the involvement of TRPC channels. Indeed, the TRPC channel inhibitor SKF-96365 prevented BDNF-induced Ca(2+) elevations and the associated I(BDNF). Thus TRPC channels emerge as novel mediators of BDNF-induced intracellular Ca(2+) elevations associated with sustained cationic membrane currents in hippocampal pyramidal neurons.
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http://dx.doi.org/10.1152/jn.00797.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806849PMC
October 2007

TRPC3 channels are necessary for brain-derived neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation.

J Neurosci 2007 May;27(19):5179-89

Department of Neurobiology, Civitan International Research Center and McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

Brain-derived neurotrophic factor (BDNF) exerts prominent effects on hippocampal neurons, but the mechanisms that initiate its actions are poorly understood. We report here that BDNF evokes a slowly developing and sustained nonselective cationic current (I(BDNF)) in CA1 pyramidal neurons. These responses require phospholipase C, IP3 receptors, Ca2+ stores, and Ca2+ influx, suggesting the involvement of transient receptor potential canonical subfamily (TRPC) channels. Indeed, I(BDNF) is absent after small interfering RNA-mediated TRPC3 knockdown. The sustained kinetics of I(BDNF) appears to depend on phosphatidylinositol 3-kinase-mediated TRPC3 membrane insertion, as shown by surface biotinylation assays. Slowly emerging membrane currents after theta burst stimulation are sensitive to the scavenger TrkB-IgG and TRPC inhibitors, suggesting I(BDNF) activation by evoked released of endogenous, native BDNF. Last, TRPC3 channels are necessary for BDNF to increase dendritic spine density. Thus, TRPC channels emerge as novel mediators of BDNF-mediated dendritic remodeling through the activation of a slowly developing and sustained membrane depolarization.
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http://dx.doi.org/10.1523/JNEUROSCI.5499-06.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806846PMC
May 2007

Transient receptor potential channels as novel effectors of brain-derived neurotrophic factor signaling: potential implications for Rett syndrome.

Pharmacol Ther 2007 Feb 21;113(2):394-409. Epub 2006 Nov 21.

Department of Neurobiology, Civitan International Research Center, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.

In addition to their prominent role as survival signals for neurons in the developing nervous system, neurotrophins have established their significance in the adult brain as well, where their modulation of synaptic transmission and plasticity may participate in associative learning and memory. These crucial activities are primarily the result of neurotrophin regulation of intracellular Ca(2+) homeostasis and, ultimately, changes in gene expression. Outlined in the following review is a synopsis of neurotrophin signaling with a particular focus upon brain-derived neurotrophic factor (BDNF) and its role in hippocampal synaptic plasticity and neuronal Ca(2+) homeostasis. Neurotrophin signaling through tropomyosin-related kinase (Trk) and pan-neurotrophin receptor 75 kD (p75(NTR)) receptors are also discussed, reviewing recent results that indicate signaling through these two receptor modalities leads to opposing cellular outcomes. We also provide an intriguing look into the transient receptor potential channel (TRPC) family of ion channels as distinctive targets of BDNF signaling; these channels are critical for capacitative Ca(2+) entry, which, in due course, mediates changes in neuronal structure including dendritic spine density. Finally, we expand these topics into an exploration of mental retardation (MR), in particular Rett Syndrome (RTT), where dendritic spine abnormalities may underlie cognitive impairments. We propose that understanding the role of neurotrophins in synapse formation, plasticity, and maintenance will make fundamental contributions to the development of therapeutic strategies to improve cognitive function in developmental disorders associated with MR.
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http://dx.doi.org/10.1016/j.pharmthera.2006.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1862519PMC
February 2007