Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome.

The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.

An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome.

BACKGROUND: Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug's effect on the cognitive and behavioral manifestations of the disorder. METHODS: Participants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η(2)) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett's post hoc testing. RESULTS: Significant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period. CONCLUSION: The clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted. TRIAL REGISTRATION: NCT01531582 - clinicaltrials.gov.

Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model.

Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal UBE3A gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular mechanisms whereby Ube3a deficiency results in AS are enigmatic. Using in vitro and in vivo systems we show dramatic changes in the expression of Ube3a following synaptic activation. In primary neuronal culture, neuronal depolarization was found to increase both nuclear and cytoplasmic Ube3a levels. Analogous up-regulation in maternal and paternal Ube3a expression was observed in Ube3a-YFP reporter mice following fear conditioning. Absence of Ube3a led to deficits in the activity-dependent increases in ERK1/2 phosphorylation, which may contribute to reported deficits in synaptic plasticity and cognitive function in AS mice. Taken together, our findings provide novel insight into the regulation of Ube3a by synaptic activity and its potential role in kinase regulation.

Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse.

The lipoprotein receptor ligand Reelin is important for the processes of normal synaptic plasticity, dendritic morphogenesis, and learning and memory. Heterozygous reeler mice (HRM) show many neuroanatomical, biochemical, and behavioral features that are associated with schizophrenia. HRM show subtle morphological defects including reductions in dendritic spine density, altered synaptic plasticity and behavioral deficits in associative learning and memory and pre-pulse inhibition. The present studies test the hypothesis that in vivo elevation of Reelin levels can rescue synaptic and behavioral phenotypes associated with HRM. We demonstrate that a single in vivo injection of Reelin increases GAD67 expression and alters dendritic spine morphology. In parallel we observed enhancement of hippocampal synaptic function and associative learning and memory. Reelin supplementation also increases pre-pulse inhibition. These results suggest that characteristics of HRM, similar to those observed in schizophrenia, are sensitive to Reelin levels and can be modified with Reelin supplementation in male and female adults.

An investigation of PreMCI: subtypes and longitudinal outcomes.

BACKGROUND/AIMS: To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI). METHODS: We longitudinally evaluated 269 elderly subjects who did not meet formal criteria for MCI at baseline but had: (1) a clinical history suggesting MCI without neuropsychological deficits (PreMCI-Clinical); or (2) neuropsychological deficits on one or more memory measures in conjunction with a negative clinical examination (amnestic PreMCI-NP) or were normal on both neuropsychological and clinical examination. RESULTS: The rate of progression to MCI or dementia over an average of 2- to 3 years was 3.7% for no cognitive impairment subjects, whereas it was significantly greater for all PreMCI subtypes (22.0% for PreMCI-Clinical, 38.9% for amnestic PreMCI-NP subjects with two or more memory impairments). Among PreMCI subjects as a whole, lower baseline scores on object memory and category fluency tests were the best predictors of progression to MCI or dementia. Cardiovascular risk factors, Parkinsonian symptoms, and hippocampal atrophy were not associated with progression. CONCLUSION: Distinct PreMCI subtypes defined on the basis of clinical and neuropsychological evaluations were found to have distinct characteristics, but both subtypes demonstrated elevated risk for progression to MCI or dementia. Despite the lack of evidence of clinical impairment, subjects with neuropsychological deficits in two memory domains were particularly at increased risk for progression of their deficits.

Adeno-associated virus-mediated rescue of the cognitive defects in a mouse model for Angelman syndrome.

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr(286) and Thr(305/306), resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients.

Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density.

Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive function; however, the in vivo effect of enhanced Reelin signaling on cognitive function and synaptic plasticity in wild-type mice is unknown. The present studies test the hypothesis that in vivo enhancement of Reelin signaling can alter synaptic plasticity and ultimately influence processes of learning and memory. Purified recombinant Reelin was injected bilaterally into the ventricles of wild-type mice. We demonstrate that a single in vivo injection of Reelin increased activation of adaptor protein Disabled-1 and cAMP-response element binding protein after 15 min. These changes correlated with increased dendritic spine density, increased hippocampal CA1 long-term potentiation (LTP), and enhanced performance in associative and spatial learning and memory. The present study suggests that an acute elevation of in vivo Reelin can have long-term effects on synaptic function and cognitive ability in wild-type mice.

Pre-MCI and MCI: neuropsychological, clinical, and imaging features and progression rates.

OBJECTIVE: To compare clinical, imaging, and neuropsychological characteristics and longitudinal course of subjects with pre-mild cognitive impairment (pre-MCI), who exhibit features of MCI on clinical examination but lack impairment on neuropsychological examination, to subjects with no cognitive impairment (NCI), nonamnestic MCI (naMCI), amnestic MCI (aMCI), and mild dementia. METHODS: For 369 subjects, clinical dementia rating sum of boxes (CDR-SB), ApoE genotyping, cardiovascular risk factors, parkinsonism (UPDRS) scores, structural brain MRIs, and neuropsychological testing were obtained at baseline, whereas 275 of these subjects received an annual follow-up for 2-3 years. RESULTS: At baseline, pre-MCI subjects showed impairment on tests of executive function and language, higher apathy scores, and lower left hippocampal volumes (HPCV) in comparison to NCI subjects. Pre-MCI subjects showed less impairment on at least one memory measure, CDR-SB and UPDRS scores, in comparison to naMCI, aMCI and mild dementia subjects. Follow-up over 2-3 years showed 28.6% of pre-MCI subjects, but less than 5% of NCI subjects progressed to MCI or dementia. Progression rates to dementia were equivalent between naMCI (22.2%) and aMCI (34.5%) groups, but greater than for the pre-MCI group (2.4%). Progression to dementia was best predicted by the CDR-SB, a list learning and executive function test. CONCLUSION: This study demonstrates that clinically defined pre-MCI has cognitive, functional, motor, behavioral and imaging features that are intermediate between NCI and MCI states at baseline. Pre-MCI subjects showed accelerated rates of progression to MCI as compared to NCI subjects, but slower rates of progression to dementia than MCI subjects.

Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation.

Considerable evidence indicates that the general blockade of protein synthesis prevents both the initial consolidation and the postretrieval reconsolidation of long-term memories. These findings come largely from studies of drugs that block ribosomal function, so as to globally interfere with both cap-dependent and -independent forms of translation. Here we show that intra-amygdala microinfusions of 4EGI-1, a small molecule inhibitor of cap-dependent translation that selectively disrupts the interaction between eukaryotic initiation factors (eIF) 4E and 4G, attenuates fear memory consolidation but not reconsolidation. Using a combination of behavioral and biochemical techniques, we provide both in vitro and in vivo evidence that the eIF4E-eIF4G complex is more stringently required for plasticity induced by initial learning than for that triggered by reactivation of an existing memory.

Insights into synaptic function from mouse models of human cognitive disorders.

Modern approaches to the investigation of the molecular mechanisms underlying human cognitive disease often include multidisciplinary examination of animal models engineered with specific mutations that spatially and temporally restrict expression of a gene of interest. This approach not only makes possible the development of animal models that demonstrate phenotypic similarities to their respective human disorders, but has also allowed for significant progress towards understanding the processes that mediate synaptic function and memory formation in the nondiseased state. Examples of successful mouse models where genetic manipulation of the mouse resulted in recapitulation of the symptomatology of the human disorder and was used to significantly expand our understanding of the molecular mechanisms underlying normal synaptic plasticity and memory formation are discussed in this article. These studies have broadened our knowledge of several signal transduction cascades that function throughout life to mediate synaptic physiology. Defining these events is key for developing therapies to address disorders of cognitive ability.