Sex representation in neurodegenerative and psychiatric disorders' preclinical and clinical studies.

Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies have requested that all trials, both at the clinical and preclinical level, use a similar number of male and female subjects to correctly interpret the results. Despite these guidelines, many studies still tend to be unbalanced in the use of male and female subjects. In this review we consider three neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and three psychiatric disorders: Depression, Attention Deficit Hyperactivity Disorder, and Schizophrenia. These disorders were chosen because of their prevalence and their recognized sex-specific differences in onset, progression, and response to treatment. Alzheimer's disease and Depression demonstrate higher prevalence in females, whereas Parkinson's Disease, Amyotrophic lateral sclerosis, Attention Deficit Hyperactivity Disorder, and schizophrenia show higher prevalence in males. Results from preclinical and clinical studies examining each of these disorders revealed sex-specific differences in risk factors, diagnostic biomarkers, and treatment response and efficacy, suggesting a role for sex-specific therapies in neurodegenerative and neuropsychiatric disorders. However, the qualitative analysis of the percentage of males and females enrolled in clinical trials in the last two decades shows that for most of the disorders, there is still a sex bias in the patients' enrolment.

Mechanisms underlying the role of DISC1 in synaptic plasticity.

Disrupted in schizophrenia 1 (DISC1) is an important hub protein, forming multimeric complexes by self-association and interacting with a large number of synaptic and cytoskeletal molecules. The synaptic location of DISC1 in the adult brain suggests a role in synaptic plasticity, and indeed, a number of studies have discovered synaptic plasticity impairments in a variety of different DISC1 mutants. This review explores the possibility that DISC1 is an important molecule for organizing proteins involved in synaptic plasticity and examines why mutations in DISC1 impair plasticity. It concentrates on DISC1's role in interacting with synaptic proteins, controlling dendritic structure and cellular trafficking of mRNA, synaptic vesicles and mitochondria. N-terminal directed mutations appear to impair synaptic plasticity through interactions with phosphodiesterase 4B (PDE4B) and hence protein kinase A (PKA)/GluA1 and PKA/cAMP response element-binding protein (CREB) signalling pathways, and affect spine structure through interactions with kalirin 7 (Kal-7) and Rac1. C-terminal directed mutations also impair plasticity possibly through altered interactions with lissencephaly protein 1 (LIS1) and nuclear distribution protein nudE-like 1 (NDEL1), thereby affecting developmental processes such as dendritic structure and spine maturation. Many of the same molecules involved in DISC1's cytoskeletal interactions are also involved in intracellular trafficking, raising the possibility that impairments in intracellular trafficking affect cytoskeletal development and vice versa. While the multiplicity of DISC1 protein interactions makes it difficult to pinpoint a single causal signalling pathway, we suggest that the immediate-term effects of N-terminal influences on GluA1, Rac1 and CREB, coupled with the developmental effects of C-terminal influences on trafficking and the cytoskeleton make up the two main branches of DISC1's effect on synaptic plasticity and dendritic spine stability.

Clinical and genetic Rett syndrome variants are defined by stable electrophysiological profiles.

BACKGROUND: Rett Syndrome (RTT) is a complex neurodevelopmental disorder, frequently associated with epilepsy. Despite increasing recognition of the clinical heterogeneity of RTT and its variants (e.g Classical, Hanefeld and PSV(Preserved Speech Variant)), the link between causative mutations and observed clinical phenotypes remains unclear. Quantitative analysis of electroencephalogram (EEG) recordings may further elucidate important differences between the different clinical and genetic forms of RTT. METHODS: Using a large cohort (n = 42) of RTT patients, we analysed the electrophysiological profiles of RTT variants (genetic and clinical) in addition to epilepsy status (no epilepsy/treatment-responsive epilepsy/treatment-resistant epilepsy). The distribution of spectral power and inter-electrode coherence measures were derived from continuous resting-state EEG recordings. RESULTS: RTT genetic variants (MeCP2/CDLK5) were characterised by significant differences in network architecture on comparing first principal components of inter-electrode coherence across all frequency bands (p < 0.0001). Greater coherence in occipital and temporal pairs were seen in MeCP2 vs CDLK5 variants, the main drivers in between group differences. Similarly, clinical phenotypes (Classical RTT/Hanefeld/PSV) demonstrated significant differences in network architecture (p < 0.0001). Right tempero-parietal connectivity was found to differ between groups (p = 0.04), with greatest coherence in the Classical RTT phenotype. PSV demonstrated a significant difference in left-sided parieto-occipital coherence (p = 0.026). Whilst overall power decreased over time, there were no difference in asymmetry and inter-electrode coherence profiles over time. There was a significant difference in asymmetry in the overall power spectra between epilepsy groups (p = 0.04) in addition to occipital asymmetry across all frequency bands. Significant differences in network architecture were also seen across epilepsy groups (p = 0.044). CONCLUSIONS: Genetic and clinical variants of RTT are characterised by discrete patterns of inter-electrode coherence and network architecture which remain stable over time. Further, hemispheric distribution of spectral power and measures of network dysfunction are associated with epilepsy status and treatment responsiveness. These findings support the role of discrete EEG profiles as non-invasive biomarkers in RTT and its genetic/clinical variants.

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

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.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

STAT1 regulates the homeostatic component of visual cortical plasticity via an AMPA receptor-mediated mechanism.

Accumulating evidence points to a role for Janus kinase/signal transducers and activators of transcription (STAT) immune signaling in neuronal function; however, its role in experience-dependent plasticity is unknown. Here we show that one of its components, STAT1, negatively regulates the homeostatic component of ocular dominance plasticity in visual cortex. After brief monocular deprivation (MD), STAT1 knock-out (KO) mice show an accelerated increase of open-eye responses, to a level comparable with open-eye responses after a longer duration of MD in wild-type (WT) mice. Therefore, this component of plasticity is abnormally enhanced in KO mice. Conversely, increasing STAT1 signaling by IFNγ treatment in WT mice reduces the homeostatic component of plasticity by impairing open-eye responses. Enhanced plasticity in KO mice is accompanied by sustained surface levels of GluA1 AMPA receptors and increased amplitude and frequency of AMPA receptor-mediated mEPSCs, which resemble changes in WT mice after a longer duration of MD. These results demonstrate a unique role for STAT1 during visual cortical plasticity in vivo through a mechanism that includes AMPA receptors.

Effects of a novel schizophrenia risk variant rs7914558 at CNNM2 on brain structure and attributional style.

BACKGROUND: A single nucleotide polymorphism (rs7914558) within the cyclin M2 (CNNM2) gene was recently identified as a common risk variant for schizophrenia. The mechanism by which CNNM2 confers risk is unknown. AIMS: To determine the impact of the rs7914558 risk 'G' allele [corrected] on measures of neurocognition, social cognition and brain structure. METHOD: Patients with schizophrenia (n = 400) and healthy controls (n = 160) completed measures of neuropsychological function and social cognition. Structural magnetic resonance imaging data were also acquired from an overlapping sample of Irish healthy controls (n = 159) and an independent sample of Italian patients (n = 82) and healthy controls (n = 39). RESULTS: No effects of genotype on neuropsychological test performance were observed. However, a dosage effect of the risk allele was found for an index of social cognition (i.e. attributional style), such that risk status was associated with reduced self-serving bias across groups (GG>AG>AA, P<0.05). Using voxel-based morphometry to investigate neuroanatomical regions putatively supporting social cognition, risk carriers had relatively increased grey matter volume in the right temporal pole and right anterior cingulate cortex (Pcorrected<0.05) in the Irish healthy controls sample; neuroanatomical associations between CNNM2 and grey matter volume in anterior cingulate cortex were also observed in the Italian schizophrenia and healthy controls samples. CONCLUSIONS: Although the biological role of CNNM2 in schizophrenia remains unknown, these data suggest that this CNNM2 risk variant rs7914558 may have an impact on neural systems relevant to social cognition. How such effects may mediate the relationship between genotype and disease risk remains to be established.

Rett syndrome in Ireland: a demographic study.

BACKGROUND: Rett syndrome (RTT) is a rare neurodevelopmental condition associated with mutations in the gene coding for the methyl-CpG-binding protein 2 (MECP2). It is primarily observed in girls and affects individuals globally. The understanding of the neurobiology of RTT and patient management has been improved by studies that describe the demographic and clinical presentation of individuals with RTT. However, in Ireland, there is a scarcity of data regarding individuals with RTT, which impedes the ability to fully characterize the Irish RTT population. Together with the Rett Syndrome Association of Ireland (RSAI), we prepared a questionnaire to determine the characteristics of RTT individuals in Ireland. Twenty-five families have participated in the study to date, providing information about demographics, genetics, familial history, clinical features, and regression. RESULTS: The results show that Irish individuals with RTT have comparable presentation with respect to individuals in other countries; however, they had a better response to anti-epileptic drugs, and fewer skeletal deformities were reported. Nonetheless, seizures, involuntary movements and regression were more frequently observed in Irish individuals. One of the main findings of this study is the limited genetic information available to individuals to support the clinical diagnosis of RTT. CONCLUSIONS: Despite the limited sample size, this study is the first to characterize the RTT population in Ireland and highlights the importance of having a swift access to genetic testing to sharpen the characterization of the phenotype and increase the visibility of Irish individuals in the international RTT community.

Development of trofinetide for the treatment of Rett syndrome: from bench to bedside.

Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the MECP2 gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with roles in epigenetic regulation of gene expression. Functional loss of MeCP2 results in abnormal neuronal maturation and plasticity, characterized by loss of verbal communication and loss of fine and gross motor function, among others. Trofinetide, a synthetic analog of glycine-proline-glutamate, was approved by the US Food and Drug Administration for the treatment of RTT in adult and pediatric patients aged 2 years and older. Here, we present the development of trofinetide from bench research to clinical studies and emphasize how the collaboration between academia, the pharmaceutical industry, and patient advocacy led to the recent approval. The bench-to-bedside development of trofinetide underscores the value of collaboration between these groups in the development and approval of treatments for rare diseases.

A NOS1 variant implicated in cognitive performance influences evoked neural responses during a high density EEG study of early visual perception.

BACKGROUND: The nitric oxide synthasase-1 gene (NOS1) has been implicated in mental disorders including schizophrenia and variation in cognition. The NOS1 variant rs6490121 identified in a genome wide association study of schizophrenia has recently been associated with variation in general intelligence and working memory in both patients and healthy participants. Whether this variant is also associated with variation in early sensory processing remains unclear. METHODS: We investigated differences in the P1 visual evoked potential in a high density EEG study of 54 healthy participants. Given both NOS1's association with cognition and recent evidence that cognitive performance and P1 response are correlated, we investigated whether NOS1's effect on P1 response was independent of its effects on cognition using CANTAB's spatial working memory (SWM) task. RESULTS: We found that carriers of the previously identified risk "G" allele showed significantly lower P1 responses than non-carriers. We also found that while P1 response and SWM performance were correlated, NOS1 continued to explain a significant proportion of variation in P1 response even when its effects on cognition were accounted for. CONCLUSION: The schizophrenia implicated NOS1 variants rs6490121 influences visual sensory processing as measured by the P1 response, either as part of the gene's pleiotropic effects on multiple aspects of brain function, or because of a primary influence on sensory processing that mediates the effects already seen in higher cognitive processes.

The effect of the neurogranin schizophrenia risk variant rs12807809 on brain structure and function.

A single nucleotide polymorphism rs12807809 located upstream of the neurogranin (NRGN) gene has been identified as a risk variant for schizophrenia in recent genome-wide association studies. To date, there has been little investigation of the endophenotypic consequences of this variant, and our own investigations have suggested that the effects of this gene are not apparent at the level of cognitive function in patients or controls. Because the impact of risk variants may be more apparent at the level of brain, the aim of this investigation was to delineate whether NRGN genotype predicted variability in brain structure and/or function. Healthy individuals participated in structural (N = 140) and/or functional (N = 36) magnetic resonance imaging (s/fMRI). Voxel-based morphometry was used to compare gray and white matter volumes between carriers of the non-risk C allele (i.e., CC/CT) and those who were homozygous for the risk T allele. Functional imaging data were acquired during the performance of a spatial working memory task, and were also analyzed with respect to the difference between C carriers and T homozygotes. There was no effect of the NRGN variant rs12807809 on behavioral performance or brain structure. However, there was a main effect of genotype on brain activity during performance of the working memory task, such that while C carriers exhibited a load-independent decrease in left superior frontal gyrus/BA10, TT individuals failed to show a similar decrease in activity. The failure to disengage this ventromedial prefrontal region, despite preserved performance, may be indicative of a reduction in processing efficiency in healthy TT carriers. Although it remains to be established whether this holds true in larger samples and in patient cohorts, if valid, this suggests a potential mechanism by which NRGN variability might contribute to schizophrenia risk.

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

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder without effective treatments. Attempts at developing targetted therapies have been relatively unsuccessful, at least in part, because the genotypical and phenotypical variability of the disorder. Therefore, identification of biomarkers of response and patients' stratification are high priorities. Administration of Insulin-like Growth Factor 1 (IGF-1) and related compounds leads to significant reversal of RTT-like symptoms in preclinical mouse models. However, improvements in corresponding clinical trials have not been consistent. A 20-weeks phase I open label trial of mecasermin (recombinant human IGF-1) in children with RTT demonstrated significant improvements in breathing phenotypes. However, a subsequent randomised controlled phase II trial did not show significant improvements in primary outcomes although two secondary clinical endpoints showed positive changes. To identify molecular biomarkers of response and surrogate endpoints, we used RNA sequencing to measure differential gene expression in whole blood samples of participants in the abovementioned phase I mecasermin trial. When all participants (n = 9) were analysed, gene expression was unchanged during the study (baseline vs. end of treatment, T0-T3). However, when participants were subclassified in terms of breathing phenotype improvement, specifically by their plethysmography-based apnoea index, individuals with moderate-severe apnoea and breathing improvement (Responder group) displayed significantly different transcript profiles compared to the other participants in the study (Mecasermin Study Reference group, MSR). Many of the differentially expressed genes are involved in the regulation of cell cycle processes and immune responses, as well as in IGF-1 signalling and breathing regulation. While the Responder group showed limited gene expression changes in response to mecasermin, the MSR group displayed marked differences in the expression of genes associated with inflammatory processes (e.g., neutrophil activation, complement activation) throughout the trial. Our analyses revealed gene expression profiles associated with severe breathing phenotype and its improvement after mecasermin administration in RTT, and suggest that inflammatory/immune pathways and IGF-1 signalling contribute to treatment response. Overall, these data support the notion that transcript profiles have potential as biomarkers of response to IGF-1 and related compounds.

Structural dynamics of synapses in vivo correlate with functional changes during experience-dependent plasticity in visual cortex.

The impact of activity on neuronal circuitry is complex, involving both functional and structural changes whose interaction is largely unknown. We have used optical imaging of mouse visual cortex responses and two-photon imaging of superficial layer spines on layer 5 neurons to monitor network function and synaptic structural dynamics in the mouse visual cortex in vivo. Total lack of vision due to dark-rearing from birth dampens visual responses and shifts spine dynamics and morphologies toward an immature state. The effects of vision after dark rearing are strongly dependent on the timing of exposure: over a period of days, functional and structural changes are temporally related such that light stabilizes spines while increasing visually driven activity. The effects of long-term light exposure can be partially mimicked by experimentally enhancing inhibitory signaling in the darkness. Brief light exposure, however, results in a rapid, transient, NMDA-dependent increase of cortical responses, accompanied by increased dynamics of dendritic spines. These findings indicate that visual experience induces rapid reorganization of cortical circuitry followed by a period of stabilization, and demonstrate a close relationship between dynamic changes at single synapses and cortical network function.

Gene expression patterns in visual cortex during the critical period: synaptic stabilization and reversal by visual deprivation.

The mapping of eye-specific, geniculocortical inputs to primary visual cortex (V1) is highly sensitive to the balance of correlated activity between the two eyes during a restricted postnatal critical period for ocular dominance plasticity. This critical period is likely to have amplified expression of genes and proteins that mediate synaptic plasticity. DNA microarray analysis of transcription in mouse V1 before, during, and after the critical period identified 31 genes that were up-regulated and 22 that were down-regulated during the critical period. The highest-ranked up-regulated gene, cardiac troponin C, codes for a neuronal calcium-binding protein that regulates actin binding and whose expression is activity-dependent and relatively selective for layer-4 star pyramidal neurons. The highest-ranked down-regulated gene, synCAM, also has actin-based function. Actin-binding function, G protein signaling, transcription, and myelination are prominently represented in the critical period transcriptome. Monocular deprivation during the critical period reverses the expression of nearly all critical period genes. The profile of regulated genes suggests that synaptic stability is a principle driver of critical period gene expression and that alteration in visual activity drives homeostatic restoration of stability.

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions.

Rett syndrome (RTT) and Fragile X syndrome (FXS) are two monogenetic neurodevelopmental disorders with complex clinical presentations. RTT is caused by mutations in the Methyl-CpG binding protein 2 gene (MECP2) altering the function of its protein product MeCP2. MeCP2 modulates gene expression by binding methylated CpG dinucleotides, and by interacting with transcription factors. FXS is caused by the silencing of the FMR1 gene encoding the Fragile X Mental Retardation Protein (FMRP), a RNA binding protein involved in multiple steps of RNA metabolism, and modulating the translation of thousands of proteins including a large set of synaptic proteins. Despite differences in genetic etiology, there are overlapping features in RTT and FXS, possibly due to interactions between MeCP2 and FMRP, and to the regulation of pathways resulting in dysregulation of common molecular signaling. Furthermore, basic physiological mechanisms are regulated by these proteins and might concur to the pathophysiology of both syndromes. Considering that RTT and FXS are disorders affecting brain development, and that most of the common targets of MeCP2 and FMRP are involved in brain activity, we discuss the mechanisms of synaptic function and plasticity altered in RTT and FXS, and we consider the similarities and the differences between these two disorders.

Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex.

Two key models for examining activity-dependent development of primary visual cortex (V1) involve either reduction of activity in both eyes via dark-rearing (DR) or imbalance of activity between the two eyes via monocular deprivation (MD). Combining DNA microarray analysis with computational approaches, RT-PCR, immunohistochemistry and physiological imaging, we find that DR leads to (i) upregulation of genes subserving synaptic transmission and electrical activity, consistent with a coordinated response of cortical neurons to reduction of visual drive, and (ii) downregulation of parvalbumin expression, implicating parvalbumin-expressing interneurons as underlying the delay in cortical maturation after DR. MD partially activates homeostatic mechanisms but differentially upregulates molecular pathways related to growth factors and neuronal degeneration, consistent with reorganization of connections after MD. Expression of a binding protein of insulin-like growth factor-1 (IGF1) is highly upregulated after MD, and exogenous application of IGF1 prevents the physiological effects of MD on ocular dominance plasticity examined in vivo.

The Role of Microglia in Neurodevelopmental Disorders and their Therapeutics.

The development of new therapeutics is critically dependent on an understanding of the molecular pathways, the disruption of which results in neurological symptoms. Genetic and biomarker studies have highlighted immune signalling as a pathway that is impaired in patients with neurodevelopmental disorders (NDDs), and several studies on animal models of aberrant neurodevelopment have implicated microglia, the brain's immune cells, in the pathology of these diseases. Despite the increasing awareness of the role of immune responses and inflammation in the pathophysiology of NDDs, the testing of new drugs rarely considers their effects in microglia. In this brief review, we present evidence of how the study of microglia can be critical for understanding the mechanisms of action of candidate drugs for NDDs and for increasing their therapeutic effect.

Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome.

Rett Syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the gene MeCP2, which is involved in the development and function of cortical networks. The clinical presentation of RTT is generally severe and includes developmental regression and marked neurologic impairment. Insulin-Like growth factor 1 (IGF1) ameliorates RTT-relevant phenotypes in animal models and improves some clinical manifestations in early human trials. However, it remains unclear whether IGF1 treatment has an impact on cortical electrophysiology in line with MeCP2's role in network formation, and whether these electrophysiological changes are related to clinical response. We performed clinical assessments and resting-state electroencephalogram (EEG) recordings in eighteen patients with classic RTT, nine of whom were treated with IGF1. Among the treated patients, we distinguished those who showed improvements after treatment (responders) from those who did not show any changes (nonresponders). Clinical assessments were carried out for all individuals with RTT at baseline and 12 months after treatment. Network measures were derived using statistical modelling techniques based on interelectrode coherence measures. We found significant interaction between treatment groups and timepoints, indicating an effect of IGF1 on network measures. We also found a significant effect of responder status and timepoint, indicating that these changes in network measures are associated with clinical response to treatment. Further, we found baseline variability in network characteristics, and a machine learning model using these measures applied to pretreatment data predicted treatment response with 100% accuracy (100% sensitivity and 100% specificity) in this small patient group. These results highlight the importance of network pathology in RTT, as well as providing preliminary evidence for the potential of network measures as tools for the characterisation of disease subtypes and as biomarkers for clinical trials.

Methyl-CpG-binding protein 2 mediates overlapping mechanisms across brain disorders.

MECP2 and its product, Methyl-CpG binding protein 2 (MeCP2), are mostly known for their association to Rett Syndrome (RTT), a rare neurodevelopmental disorder. Additional evidence suggests that MECP2 may underlie other neuropsychiatric and neurological conditions, and perhaps modulate common presentations and pathophysiology across disorders. To clarify the mechanisms of these interactions, we develop a method that uses the binding properties of MeCP2 to identify its targets, and in particular, the genes recognized by MeCP2 and associated to several neurological and neuropsychiatric disorders. Analysing mechanisms and pathways modulated by these genes, we find that they are involved in three main processes: neuronal transmission, immuno-reactivity, and development. Also, while the nervous system is the most relevant in the pathophysiology of the disorders, additional systems may contribute to MeCP2 action through its target genes. We tested our results with transcriptome analysis on Mecp2-null models and cells derived from a patient with RTT, confirming that the genes identified by our procedure are directly modulated by MeCP2. Thus, MeCP2 may modulate similar mechanisms in different pathologies, suggesting that treatments for one condition may be effective for related disorders.