1. Introduction
Basic research in the field of neurogenetic disorders will continue to expand our
knowledge concerning the development and function of the nervous system. The greatest
challenges in the field of neurogenetic disorders are defining the molecular mechanisms
by which genetic mutations confer disease risk and phenotype. Neural plasticity involves
a series of dynamic cellular events that orchestrate structural and functional alterations
in response to experience. The study of neural plasticity provides a basic and powerful
approach for unraveling the complexities of the nervous system. Investigations of
plastic changes in neurogenetic diseases will shed light on the molecular and cellular
mechanisms that govern function of the nervous system, in turn, leading to the discovery
of potential therapeutic targets for conditions including mental impairment, neurodegeneration,
epilepsy, and autism.
This special issue has targeted the most recent developments in neural plasticity
as regards neurogenetic disorders. More than twenty laboratories worldwide have contributed
to this special issue. The contributions have showcased the current efforts in understanding
neural plastic changes and the underlying molecular and cellular mechanisms in patients
and animal models of neurogenetic disorders, including a wide range of neurodevelopmental
and neurodegenerative diseases. Additionally, the most promising therapeutic strategies
for treating these disorders have been reviewed.
2. Plasticity in Neurogenetic Disorders
Fragile X syndrome (FXS), the most common inherited form of mental impairment and
autism spectrum disorders (ASDs), is predominantly caused by a CGG repeat expansion
in the 5′-UTR of the FMR1 gene, which encodes the fragile X mental retardation protein
(FMRP). With astrocytes playing a pivotal role in the development of synapses in central
nervous system, C. Cheng et al. reviewed the current knowledge about the biology of
astrocytes and highlighted their involvement in the developmental plasticity of FXS.
Martin and Huntsman summarized studies on the mechanisms underlying plasticity deficits
in FXS and emphasized that characterizing early developmental deficits in plasticity
is fundamental to developing therapies for the disorder. K. Kelley et al. reviewed
the studies of repeat-associated miRNAs (ramRNAs) in the transgenic zebrafish model
and reported that ramRNA-induced DNA methylation of the FMR1 5′-UTR CGG trinucleotide
repeat expansion is central to the etiology of FXS. Studies in animal models and patients
have indicated that the tetracycline derivative minocycline may hold great therapeutic
promise for FXS. Minocycline is thought to act via the inhibition of matrix metalloproteinases
(MMPs), the zinc-dependent extracellular proteases involved in tissue remodeling and
cell-cell signaling. S. S. Siller and K. Broadie summarized the recent studies on
minocycline action in Drosophila and mouse FXS models as well as in patients, and
discussed a proposed mechanism of minocycline action as an MMP inhibitor.
Rett Syndrome is a progressive neurological disorder caused by mutations in the X-linked
MECP2 gene. MeCP2 was originally known to bind methylated DNA and interact with repressor
complexes to inhibit and silence its genomic targets. However, new studies have challenged
this idea. R. M. Zachariah and M. Rastegar summarized the current knowledge regarding
the molecular function of MeCP2 and pointed out that a collaborative effort between
basic scientists and clinicians is required to address the novel and challenging concepts
in MeCP2 research and to develop effective therapies for Rett Syndrome. Alterations
in dendritic spines have been documented in Rett syndrome; however, C. A. Chapleau
et al. reported that the lower dendritic spine density is only apparent in hippocampal
CA1 pyramidal neurons of Mecp2 mutant mice at a presymptomatic stage. This finding
suggests that dendritic spine density in hippocampal neurons should not be used as
a phenotypic endpoint for the evaluation of therapeutic interventions in symptomatic
Mecp2-deficient mice and questions the role of MeCP2 in later stages of excitatory
synapse and dendritic spine maintenance. The X-linked serine/threonine kinase cyclin-dependent
kinase-like 5 (CDKL5) has been associated with early-onset epileptic encephalopathies
characterized by intractable epilepsy, severe developmental delay, and the presence
of Rett-syndrome-like features. C. Kilstrup-Nielsen et al. reviewed the current state
of CDKL5 research with an emphasis on the clinical symptoms associated with mutations
in CDKL5 and the molecular mechanisms of CDKL5 function in neuronal plasticity.
Down syndrome is a neurodevelopmental disorder caused by triplication of chromosome
21 and is characterized by neurocognitive defects that range from severe intellectual
disability to various patterns of neuropsychological deficits. N. Créau reviewed the
main molecular and cellular findings observed in mouse models of Down syndrome and
described their relationship to disease phenotypes. N. Rueda et al. also summarized
studies utilizing Down syndrome mouse models but from the perspective of investigating
the neurobiological substrates of mental disability in Down syndrome and testing therapies
that could improve cognition. N. Cramer and Z. Galdzicki focused on hippocampal networks
which are particularly impacted in Down syndrome, highlighted the neurophysiological
changes that reduce the ability of trisomic neurons to undergo neural plastic adaptations,
and discussed how altered plasticity may contribute to the cognitive disabilities
in Down syndrome patients. Excessive GABAergic neurotransmission dampens hippocampal
synaptic plasticity and contributes to cognitive impairments. Treatment with GABAA
receptor antagonists results in increased plasticity and improved memory deficits
in Down syndrome mice. The selective serotonin reuptake inhibitor fluoxetine can enhance
plasticity in the adult rodent brain by attenuating GABAergic inhibition. Unexpectedly,
M. Heinen et al. reported that adult-onset fluoxetine treatment does not improve behavioral
impairments and even shows adverse seizure and mortality effects in Down syndrome
mice raising the possibility of a drug/genotype interaction.
Angelman syndrome is a neurodevelopmental disorder caused by deletion or loss-of-function
mutations in the maternally inherited UBE3A gene and is characterized by severe mental
impairment, lack of speech, ataxia, susceptibility to seizures, and unique behavioral
features. The UBE3A gene product Ube3a plays an important role in synaptic function
and in regulation of activity-dependent synaptic plasticity. N. R. Jana summarized
various animal models of Angelman syndrome and discussed how these models provide
fundamental insight into understanding the disease biology for potential therapeutic
intervention. Tuberous sclerosis complex (TSC) is caused by mutation of either the
Tsc1 or Tsc2 genes, which can lead to the disinhibition of mammalian target of rapamycin
(mTOR). T. Kirschstein described the animal models that have been established for
tuberous sclerosis complex and discussed observed alterations in synaptic plasticity
and learning in these models. Charcot-Marie-Tooth disease represents a large group
of inherited peripheral neuropathies that involve both motor and sensory nerves and
induce muscular atrophy and weakness. P. Juárez and F. Palau summarized the neural
and molecular features of Charcot-Marie-Tooth Disease and pointed out that our understanding
of the molecular pathways involved in the disease has helped to identify molecular
targets for designing novel therapeutic approaches. Copy-number variations (CNVs)
in the genome have been identified in several psychiatric disorders including ASDs
and schizophrenia. J. Nomura and T. Takumi reviewed the creation of CNV-based animal
models of psychiatric disorders and the corresponding neuroanatomical and behavioral
abnormalities in these models that provide insight into human neuropsychiatric disorders.
Huntington disease is a neurodegenerative disorder caused by a tandem repeat expansion
encoding a polyglutamine tract in the huntingtin protein. R. Vlamings et al. discussed
the behavioral, neurophysiological, and histopathological phenotypes of transgenic
Huntington disease rats that carry a truncated huntingtin cDNA fragment with 51 CAG
repeats under control of the native rat huntingtin promoter. Different brain regions,
including the hippocampus, cerebral cortex, and striatum, are affected in Huntington
disease. M. I. Ransome et al. reviewed the hippocampal abnormalities, in particular
the deficits of adult neurogenesis in transgenic Huntington disease mice, and discussed
potential mechanisms underlying disrupted hippocampal neurogenesis and how deficits
in cellular plasticity may contribute to cognitive and affective symptoms in Huntington
disease.
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder
caused by a mutation or deletion in the survival motor neuron-1 (SMN1) gene. L.-K.
Tsai summarized the SMN-independent therapeutic targets and strategies with demonstrated
potential for the treatment of SMA. Spinal and bulbar muscular atrophy is a polyglutamine
disease characterized by progressive muscle weakness and atrophy of the bulbar, facial,
and limb muscles pathologically associated with motor neuron loss in the spinal cord
and brainstem. Polyglutamine expansion within the androgen receptor is a disease-causing
protein that results in spinal and bulbar muscular atrophy. F. Tanaka et al. reviewed
current therapeutic strategies for spinal and bulbar muscular atrophy, including those
based on the native functions of the androgen receptor. Amyotrophic lateral sclerosis
is a neurodegenerative disease principally affecting motor neurons. Besides motor
symptoms, patients may develop cognitive disturbances or even frontotemporal dementia,
indicating that amyotrophic lateral sclerosis may also involve brain regions outside
of the motor regions. F. Trojsi et al. reviewed the current knowledge concerning the
neuropsychological and neuropathological sequelae of amyotrophic lateral sclerosis,
with a special focus on the neuroimaging findings associated with cognitive change.
Human diseases can now be modeled with relevant cell populations derived from induced
pluripotent stem cells (iPSCs) that are generated with techniques that reprogram the
somatic cells of patients. H. Wang and L. C. Doering reviewed recent studies using
iPSCs to model various neurogenetic disorders and summarized the therapeutic implications
of iPSCs, including drug screening and cell therapy for neurogenetic disorders. They
highlighted the key issues associated with reprogramming that must be addressed before
iPSC technology can translate to the clinic. Brain-derived neurotrophic factor (BDNF)
plays essential roles in neuronal development, plasticity, and survival. Investigating
the trafficking and release of BDNF is essential for understanding and potentially
treating neurological disorders. D. Hartmann et al. summarized multiple techniques
to investigate the transport and activity-dependent release of BDNF and their application
in neurogenetic disorders. mTOR is a protein kinase involved in many neuronal functions,
including dendritogenesis, plasticity, and protein synthesis. The recent literature
on the neurological conditions associated with dysregulation of mTOR was covered by
T. T. Gipson and M. V. Johnston. In addition, clinical trials for neurogenetic disorders
with abnormalities in synaptic plasticity, and mTOR signaling were discussed.
3. Conclusion
Over the past decade, we have witnessed a dynamic expansion in the study of neurogenetic
disorders. This special issue is by no means exhaustive of the research in this exciting
field. We hope that the papers published herein will give our readers a broad sense
of the recent progress in the field of plasticity in neurogenetic disorders as well
as inspire future work that will provide a better understanding of the disease mechanisms
and eventually lead to more effective treatments.