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1.  Repeated Insulin-Like Growth Factor 1 Treatment in a Patient with Rett Syndrome: A Single Case Study 
Rett syndrome (RTT) is a devastating neurodevelopmental disorder that has no cure. Patients show regression of acquired skills, motor, and speech impairment, cardio-respiratory distress, microcephaly, and stereotyped hand movements. The majority of RTT patients display mutations in the gene that codes for the Methyl-CpG binding protein 2 (MeCP2), which is involved in the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function are good candidates for ameliorating the symptoms of RTT. In particular, insulin-like growth factor 1 (IGF1) and its active peptide (1–3) IGF1 cross the Blood Brain Barrier, and therefore are ideal treatments for RTT Indeed, both (1–3) IGF1 and IGF1 treatment significantly ameliorates RTT symptoms in a mouse model of the disease In a previous study, we established that IGF1 is safe and well tolerated on Rett patients. In this open label clinical case study, we assess the safety and tolerability of IGF1 administration in two cycles of the treatment. Before and after each cycle, we monitored the clinical and blood parameters, autonomic function, and social and cognitive abilities, and we found that IGF1 was well tolerated each time and did not induce any side effect, nor it interfered with the other treatments that the patient was undergoing. We noticed a moderate improvement in the cognitive, social, and autonomic abilities of the patient after each cycle but the benefits were not retained between the two cycles, consistent with the pre-clinical observation that treatments for RTT should be administered through life. We find that repeated IGF1 treatment is safe and well tolerated in Rett patients but observed effects are not retained between cycles. These results have applications to other pathologies considering that IGF1 has been shown to be effective in other disorders of the autism spectrum.
PMCID: PMC4042280  PMID: 24918098
Rett syndrome; insulin-like growth factor 1; social cognition; seizures; autonomic functions
2.  An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis 
Human Molecular Genetics  2014;23(12):3316-3326.
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.
PMCID: PMC4030770  PMID: 24474471
3.  New Challenges and Frontiers in the Research for Neuropsychiatric Disorders 
PMCID: PMC3397317  PMID: 22811670
4.  IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients 
Autism Research and Treatment  2012;2012:679801.
Rett syndrome (RTT) is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2). Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1), are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3) IGF1, cross the blood brain barrier, and (1–3) IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy). This study shows that there are no risks associated with IGF1 administration.
PMCID: PMC3420537  PMID: 22934177
5.  miR-132, an experience-dependent microRNA, is essential for visual cortex plasticity 
Nature neuroscience  2011;14(10):1240-1242.
Using multiple quantitative analyses, we discovered microRNAs (miRNAs) abundantly expressed in visual cortex that respond to dark-rearing (DR) and/or monocular deprivation (MD). The most significantly altered miRNA, miR-132, was rapidly upregulated after eye-opening and delayed by DR. In vivo inhibition of miR-132 prevented ocular dominance plasticity in identified neurons following MD, and affected maturation of dendritic spines, demonstrating its critical role in the plasticity of visual cortex circuits.
PMCID: PMC3183341  PMID: 21892155
6.  Experience-dependent plasticity in visual cortex 
To determine the relationship between synaptic structural changes and cortical function, we recently published a study where we imaged dendritic spines using two-photon in vivo microscopy while monitoring network activity in the visual cortex using intrinsic signal imaging. By manipulating cortical activity levels by dark-rearing mice and re-exposing them to light, we found a close inverse correspondence between dendritic spine structural dynamics and visually evoked cortical function on a timescale of days. Light exposure following dark-rearing slowly increased visually evoked cortical processing and stabilized dendritic spine structure, an effect partially mimicked by diazepam injections in dark reared mice suggesting that this slow recovery is mediated by inhibitory signaling. Surprisingly, very brief (2 h) periods of light exposure led to an NMDA-dependent rapid reorganization of cortical networks with an early emergence of visually-evoked cortical activation and enhanced spine dynamics. Here we further explore the relationship between spine morphology and visual function.
PMCID: PMC3104584  PMID: 21655445
dendritic spine; visual cortex; dark-rearing; synapse; intrinsic signal imaging; two-photon imaging
7.  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.
PMCID: PMC2932955  PMID: 20720116
Imaging; dendritic spine; dark rearing; light; synapse; inhibition
8.  Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation 
Nature neuroscience  2010;13(4):450-457.
A myriad of mechanisms are suggested to account for the full richness of visual cortical plasticity. We report that visual cortex lacking Arc is impervious to the effects of deprivation or experience. Using intrinsic signal imaging and chronic visually evoked potential recordings, we find that Arc−/− mice do not exhibit depression of deprived eye responses or a shift in ocular dominance after brief monocular deprivation. Extended deprivation also fails to elicit a shift in ocular dominance or open eye potentiation. Moreover, Arc−/− mice lack stimulus–selective response potentiation. Although Arc−/− mice exhibit normal visual acuity, baseline ocular dominance is abnormal and resembles that observed after dark–rearing. These data suggest that Arc is required for the experience–dependent processes that normally establish and modify synaptic connections in visual cortex.
PMCID: PMC2864583  PMID: 20228806
9.  Molecular mechanisms of experience-dependent plasticity in visual cortex 
A remarkable amount of our current knowledge of mechanisms underlying experience-dependent plasticity during cortical development comes from study of the mammalian visual cortex. Recent advances in high-resolution cellular imaging, combined with genetic manipulations in mice, novel fluorescent recombinant probes, and large-scale screens of gene expression, have revealed multiple molecular mechanisms that underlie structural and functional plasticity in visual cortex. We situate these mechanisms in the context of a new conceptual framework of feed-forward and feedback regulation for understanding how neurons of the visual cortex reorganize their connections in response to changes in sensory inputs. Such conceptual advances have important implications for understanding not only normal development but also pathological conditions that afflict the central nervous system.
PMCID: PMC2674480  PMID: 18977729
ocular dominance plasticity; critical period; synapses; feed-forward regulation; feedback regulation; homeostasis

Results 1-9 (9)