Constance L. Smith-Hicks

Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD

Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca(2+)/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.

Activity-Induced Notch Signaling in Neurons Requires Arc/Arg3.1 and Is Essential for Synaptic Plasticity in Hippocampal Networks

Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Thus, Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the synaptic plasticity that contributes to memory formation.

A double blind randomized placebo control trial of levetiracetam in Tourette syndrome.

The objective of this study was to investigate the effectiveness of levetiracetam for the treatment of tics in children with Tourette syndrome (TS). Levetiracetam, an atypical anticonvulsant, has been suggested in open‐label protocols to be an effective tic‐suppressing agent in individuals with TS. A double blind, randomized, placebo‐controlled, cross‐over trial was performed to investigate this medication in children with moderate to moderately‐severe tics. Subjects received, in a randomized sequence, 4‐weeks of levetiracetam (maximum dose 30 mg/kg/day) or placebo, with a 2‐week intervening washout period between cycles. Primary outcome measures included two separate scales from the Yale Global Tic Severity Scale; the Total Tic score and the Total overall score. Measures were assessed at baseline, prior to randomization, on Day 28 (end of Phase 1), on Day 42 (baseline for second phase) and on Day 70 (end of Phase 2). Twenty‐two subjects (21 boys and 1 girl) with TS, mean age 12.2 ± 2.3 years, range 8 to 16 years, participated. A mild reduction in tics occurred during both the levetiracetam and placebo treatment phases. There was no significant difference between treatments and no evidence of sequence or cross‐over effects. In conclusion, Levetiracetam is not more beneficial than placebo in suppressing tics in children with TS.

SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells

It has been suggested that gene expression and protein synthesis are required for both long-term memory consolidation and late phases of long-term potentiation and long-term depression (LTD). The necessary genes and the specific transcription factor binding sites in their promoters remain unknown. We found that inhibition of the transcription factor SRF or its cofactor MAL blocked the late phase of LTD in mouse cultured cerebellar Purkinje cells, as did deletion of the immediate early gene Arc. Using neuronal bacterial artificial chromosome (BAC) transfection, we found that, in Arc−/− cells transfected with a wild-type Arc BAC, late-phase LTD was rescued. However, mutation of one SRF-binding site in the Arc promoter (SRE 6.9) blocked this rescue. Co-transfection of wild-type Arc and SRF engineered to bind mutated SRE 6.9 restored late-phase LTD in Arc−/−, SRE 6.9 mutant BAC cells. Thus, SRF binding to SRE 6.9 in the Arc promoter is required for the late phase of cerebellar LTD.

GABAergic dysfunction in pediatric neuro-developmental disorders.

The GABAergic system is central to the development and functional maturation of the nervous system. Emerging evidence support the role of GABAergic dysfunction in neuro-developmental disorders. This review presents the molecules and mechanisms that underlie GABA system dysfunction in several neuro-developmental disorders presenting in childhood. The impact on synaptic plasticity, neuronal circuit function and behavior, followed by targeted treatment strategies are discussed.

Increased Sparsity of Hippocampal CA1 Neuronal Ensembles in a Mouse Model of Down Syndrome Assayed by Arc Expression

Down syndrome (DS) is the leading chromosomal cause of intellectual disability, yet the neural substrates of learning and memory deficits remain poorly understood. Here, we interrogate neural networks linked to learning and memory in a well-characterized model of DS, the Ts65Dn mouse. We report that Ts65Dn mice exhibit exploratory behavior that is not different from littermate wild-type (WT) controls yet behavioral activation of Arc mRNA transcription in pyramidal neurons of the CA1 region of the hippocampus is altered in Ts65Dn mice. In WT mice, a 5 min period of exploration of a novel environment resulted in Arc mRNA transcription in 39% of CA1 neurons. By contrast, the same period of exploration resulted in only ~20% of CA1 neurons transcribing Arc mRNA in Ts65Dn mice indicating increased sparsity of the behaviorally induced ensemble. Like WT mice the CA1 pyramidal neurons of Ts65Dn mice reactivated Arc transcription during a second exposure to the same environment 20 min after the first experience, but the size of the reactivated ensemble was only ~60% of that in WT mice. After repeated daily exposures there was a further decline in the size of the reactivated ensemble in Ts65Dn and a disruption of reactivation. Together these data demonstrate reduction in the size of the behaviorally induced network that expresses Arc in Ts65Dn mice and disruption of the long-term stability of the ensemble. We propose that these deficits in network formation and stability contribute to cognitive symptoms in DS.

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome

SATB2‐associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in‐depth phenotypic characterization or genotype‐phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high‐arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

Randomized open-label trial of dextromethorphan in Rett syndrome

Objective: To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome. Methods: We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist–Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity. Results: Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale. Conclusions: Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome. Classification of evidence: This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.

A PIGH mutation leading to GPI deficiency is associated with developmental delay and autism

We identified an individual with a homozygous missense variant (p.Ser103Pro) in a conserved residue of the glycosylphosphatidylinositol (GPI) biosynthesis gene PIGH. This gene encodes an essential component of the phosphatidylinositol N‐acetylglucosaminyltransferase complex, in the first step of the biosynthesis of GPI, a glycolipid anchor added to more than one hundred human proteins, several being critical for embryogenesis and neurological functions. The affected individual had hypotonia, moderate developmental delay, and autism. Unlike other reported individuals with GPI deficiency, the proband did not have epilepsy; however, he did have two episodes of febrile seizures. He had normal alkaline phosphatase and no brachytelephalangy. Upon analysis of the surface expression of GPI‐anchored proteins on granulocytes, he was demonstrated to have GPI deficiency. This suggests that PIGH mutations may cause a syndrome with developmental delay and autism, but without an epileptic encephalopathy, and should increase the awareness of the potentially deleterious nature of biallelic variants in this gene.

CHAPTER G1 – Tourette Syndrome

Tourette syndrome (TS) is a common, inherited neuropsychiatric disorder, characterized by the presence of chronic involuntary motor and vocal tics that wax and wane. In addition to tics, individuals with this syndrome often have a variety of concomitant psychopathologies, including obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD), learning difficulties, and sleep abnormalities. TS is an inherited disorder, but the genetic abnormality and precise mode of transmission remain undetermined. Understanding of a role for nongenetic environmental influences is also evolving. The precise neuroanatomical localization remains unknown, but data suggest involvement of cortico-striatothalamo- cortical (CSTC) circuits. At a cellular level, the distribution of classical neurotransmitters within CSTC circuits raises the possibility that a variety of transmitters could be involved in the pathobiology of TS. Although abnormalities occur within dopaminergic systems, the precise cellular mechanism is not yet identified. An immune-mediated mechanism remains an unproven hypothesis. Active research continues, and the availability of animal models would be of major benefit.