The Therapeutic effect of Memantine through the Stimulation of Synapse Formation and Dendritic Spine Maturation in Autism and Fragile X Syndrome

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs

Effects of low-frequency whole-body vibration on motor-evoked potentials in healthy men.

addresses: Sport and Exercise Science Research Centre, Faculty of Engineering, Science and The Built Environment, London South Bank University, 103 Borough Road, London SE1 0AA, UK. [email protected] is the author's post-print version of an article published in Experimental Physiology, 2009, Vol. 94, Issue 1, pp. 103 - 116 Copyright © 2009 Wiley-Blackwell /The Physiological Society. The definitive version is available at www3.interscience.wiley.comThe aim of this study was to determine whether low-frequency whole-body vibration (WBV) modulates the excitability of the corticospinal and intracortical pathways related to tibialis anterior (TA) muscle activity, thus contributing to the observed changes in neuromuscular function during and after WBV exercise. Motor-evoked potentials (MEPs) elicited in response to transcranial magnetic stimulation (TMS) of the leg area of the motor cortex were recorded in TA and soleus (SOL) muscles of seven healthy male subjects whilst performing 330 s continuous static squat exercise. Each subject completed two conditions: control (no WBV) and WBV (30 Hz, 1.5 mm vibration applied from 111 to 220 s). Five single suprathreshold and five paired TMS were delivered during each squat period lasting 110 s (pre-, during and post-WBV). Two interstimulus intervals (ISIs) between the conditioning and the testing stimuli were employed in order to study the effects of WBV on short-interval intracortical inhibition (SICI, ISI = 3 ms) and intracortical facilitation (ICF, ISI = 13 ms). During vibration relative to squat exercise alone, single-pulse TMS provoked significantly higher TA MEP amplitude (56 +/- 14%, P = 0.003) and total area (71 +/- 19%, P = 0.04), and paired TMS with ISI = 13 ms provoked smaller MEP amplitude (-21 +/- 4%, P = 0.01) but not in SOL. Paired-pulse TMS with ISI = 3 ms elicited significantly lower MEP amplitude (TA, -19 +/- 4%, P = 0.009; and SOL, -13 +/- 4%, P = 0.03) and total area (SOL, -17 +/- 6%, P = 0.02) during vibration relative to squat exercise alone in both muscles. Tibialis anterior MEP facilitation in response to single-pulse TMS suggests that WBV increased corticospinal pathway excitability. Increased TA and SOL SICI and decreased TA ICF in response to paired-pulse TMS during WBV indicate vibration-induced alteration of the intracortical processes as well

Reflexiones universitarias. San Pedro Valencia: renovación urbana, saneamiento ambiental y emprendimientos turísticos. Otoño 2015

Los trabajos que aquí se presentan se elaboraron por las y los estudiantes como parte de las actividades del Proyecto de Aplicación Profesional (PAP) “San Pedro Valencia: renovación urbana, saneamiento ambiental y emprendimientos turísticos”, durante el periodo de Otoño de 2015. A lo largo del periodo los autores compartieron sus reflexiones en torno a su percepción sobre el contexto en el que actúa el PAP; sobre las alternativas posibles a la problemática detectada y lo que significa pensar una alternativa; sobre los sujetos con los que se ha interactuado a lo largo de la experiencia de trabajo y sobre el papel del profesionista y del ciudadano en un mundo como el que nos tocó vivir. La obra está compuesta por reflexiones personales de las y los estudiantes que, explorando estas temáticas, comparten sus aprendizajes y observaciones de forma vívida.ITESO, A.C

Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia

Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function

Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.

Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg block. In addition, we provide new views on Mg and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2B unusually allowed Mg permeation, whereas nearby N615I reduced Ca permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations

Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial

<p>Abstract</p> <p>Background</p> <p>Several uncontrolled studies of hyperbaric treatment in children with autism have reported clinical improvements; however, this treatment has not been evaluated to date with a controlled study. We performed a multicenter, randomized, double-blind, controlled trial to assess the efficacy of hyperbaric treatment in children with autism.</p> <p>Methods</p> <p>62 children with autism recruited from 6 centers, ages 2–7 years (mean 4.92 ± 1.21), were randomly assigned to 40 hourly treatments of either hyperbaric treatment at 1.3 atmosphere (atm) and 24% oxygen ("treatment group", n = 33) or slightly pressurized room air at 1.03 atm and 21% oxygen ("control group", n = 29). Outcome measures included Clinical Global Impression (CGI) scale, Aberrant Behavior Checklist (ABC), and Autism Treatment Evaluation Checklist (ATEC).</p> <p>Results</p> <p>After 40 sessions, mean physician CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0008), receptive language (p < 0.0001), social interaction (p = 0.0473), and eye contact (p = 0.0102); 9/30 children (30%) in the treatment group were rated as "very much improved" or "much improved" compared to 2/26 (8%) of controls (p = 0.0471); 24/30 (80%) in the treatment group improved compared to 10/26 (38%) of controls (p = 0.0024). Mean parental CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0336), receptive language (p = 0.0168), and eye contact (p = 0.0322). On the ABC, significant improvements were observed in the treatment group in total score, irritability, stereotypy, hyperactivity, and speech (p < 0.03 for each), but not in the control group. In the treatment group compared to the control group, mean changes on the ABC total score and subscales were similar except a greater number of children improved in irritability (p = 0.0311). On the ATEC, sensory/cognitive awareness significantly improved (p = 0.0367) in the treatment group compared to the control group. Post-hoc analysis indicated that children over age 5 and children with lower initial autism severity had the most robust improvements. Hyperbaric treatment was safe and well-tolerated.</p> <p>Conclusion</p> <p>Children with autism who received hyperbaric treatment at 1.3 atm and 24% oxygen for 40 hourly sessions had significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children who received slightly pressurized room air.</p> <p>Trial Registration</p> <p>clinicaltrials.gov NCT00335790</p