Synaptic Plasticity in Mouse Models of Autism Spectrum Disorders

Analysis of synaptic plasticity together with behavioral and molecular studies have become a popular approach to model autism spectrum disorders in order to gain insight into the pathosphysiological mechanisms and to find therapeutic targets. Abnormalities of specific types of synaptic plasticity have been revealed in numerous genetically modified mice that have molecular construct validity to human autism spectrum disorders. Constrained by the feasibility of technique, the common regions analyzed in most studies are hippocampus and visual cortex. The relevance of the synaptic defects in these regions to the behavioral abnormalities of autistic like behaviors is still a subject of debate. Because the exact regions or circuits responsible for the core features of autistic behaviors in humans are still poorly understood, investigation using region-specific conditional mutant mice may help to provide the insight into the neuroanatomical basis of autism in the future.     

THE EFFECT OF REPETITIVE ELECTRICAL STIMULATION ON THE MOTOR EVOKED HEMODYNAMIC RESPONSES

The aim of this study was to investigate the influence of short-term repetitive electrical stimulation (rES training session) on the motor-evoked hemodynamic responses. The fMRI echo-planar images (EPI) were recorded before and after the rES training. The right median nerve (MN) was stimulated during rES. The rES training resulted in a significant increase in activity in a number of supraspinal regions, including sensorimotor and associative cortical areas. On the subcortical level, the effect was also found in the cerebellum, the midbrain, and the thalamus. Possible mechanisms of the neuronal plastic changes observed after rES, and memory processes involved in learning are discussed.     

Functional Analysis of Dynamin Isoforms in Drosophila Melanogaster

Dynamin and dynamin-like proteins are required for endocytosis. synaptic vesicle recycling and membrane trafficking. From the shibire locus in Drosophila melanogaster, six different isoforms of dynamin are generated by alternative splicing. However, the roles of the individual isoforms in cellular processes are unknown. To investigate functional differences among the dynamin isoforms, transgenic lines were generated that individually expressed each of 3 different isoforms under UAS^GAL4 control. The expression of the isoforms was controlled by neural promoter (elav)-driven GAL4, or by a shibire-promoter driven GAL4 transgene. Reporter gene expression indicated that the shi promoter is active during embryogenesis, and in larvae, pupae, and adults in a pattern consistent with normal dynamin expression. To assay for the ability of dynamin isoforms to function in vivo, the isoforms expressed via these GAL4 drivers were tested for the ability to rescue shibire phenotypes. When expressed at very high levels all individual isoforms tested rescued the temperature-sensitive paralytic phenotype of shl^ls2 flies; however, this rescue was partial, suggesting that no single tested isoform is sufficient for synaptic vesicle recycling in vivo. When tested for ability to rescue lethality induced by heat-pulsing larvae during development, shi- promoter driven expression of individual isoforms conferred significant resistance to heat treatment during larval development. However, all 3 isoforms were unable to rescue the lethality of shi^12-12B mutants which are severely hypomorphic (or null) for shibire function. Taken together. these observations suggest that individual shibire isoforms have specific molecular activities in vivo.     

High-plasticity mesenchymal stem cells isolated from adult-retained primary teeth and autogenous adult tooth pulp—A potential source for regenerative therapies?

PurposeThe objective of this study was to compare the growth rate, morphology, immunohistology and plasticity of autogenous adult-retained SHEDs (arSHEDs) and adult dental pulp stem cells (DPSCs) obtained from the same donor.MethodsExpression of the mesenchymal stem cell markers CD44, CD90, CD105, caspase-3 and GAPDH were assessed using RT-PCR. Caspase-3 and CD44 were also evaluated at the protein level by western blotting of cell lysates. Plasticity of DPSCs and arSHEDs were tested by culture in adipogenic, chondrogenic, osteogenic and Schwann cells induction media.ResultsDPSCs and arSHEDs were isolated by explant culturing and were similarly positive for growth rate and all tested markers. Furthermore, DPSCs and arSHEDs could be driven to adipocyte, chondrocyte, osteocyte and Schwann cells lineages thus indicating similar plasticity as precursor cells.ConclusionThis study demonstrates the similarities between DPSCs and arSHEDs in a unique situation, where both stem cells (SC) types were obtained from a single patient and thus represent an alternative source of SC’s for tissue engineering and regeneration.     

Effect of transcranial direct current stimulation on neuroplasticity in corticomotor pathways of the tongue muscles

The aim of this study is to investigate effects of transcranial direct current stimulation (tDCS) on neuroplasticity in corticomotor pathways related to tongue muscles evoked by a training task using the tongue drive system (TDS). Using a crossover design, 13 healthy participants completed two sessions of tDCS while performing 30 min of TDS training. Sessions were spaced at least 2 weeks apart and participants randomly received anodal and sham tDCS stimulation in the first session and the other condition in the second session. Single and paired pulse transcranial magnetic stimulation was used to elicit motor evoked potentials (MEPs) of the tongue at three time‐points: before, immediately after and 30 min after training. Participant‐based reports of fun, pain, fatigue and motivation, level of difficulty and effort were evaluated on numerical rating scales. There was no consistent significant effect of anodal and sham stimulation on single or paired pulse stimulation MEP amplitude immediately or 30 min after TDS training. Irrespective of tDCS type, training with TDS induced cortical plasticity in terms of increased MEP amplitudes for higher stimulus intensities after 30 min compared with before and immediately after training. Participant‐based reports revealed no significant difference between tDCS conditions for level of fun, fatigue, motivation, difficulty and level of effort but a significant increase in pain in the anodal condition, although pain level was low for both conditions. In conclusion, tongue MEP amplitudes appear to be sensitive to training with the tongue using TDS; however, anodal tDCS does not have an impact on training‐evoked neuroplasticity of tongue corticomotor pathways.     

Division of labour in honey bees: age‐ and task‐related changes in the expression of octopamine receptor genes

The honey bee (Apis mellifera L.) has developed into an important ethological model organism for social behaviour and behavioural plasticity. Bees perform a complex age‐dependent division of labour with the most pronounced behavioural differences occurring between in‐hive bees and foragers. Whereas nurse bees, for example, stay inside the hive and provide the larvae with food, foragers leave the hive to collect pollen and nectar for the entire colony. The biogenic amine octopamine appears to play a major role in division of labour but the molecular mechanisms involved are unknown. We here investigated the role of two characterized octopamine receptors in honey bee division of labour. AmOctαR1 codes for a Ca²⁺‐linked octopamine receptor. AmOctβR3/4 codes for a cyclic adenosine monophosphate‐coupled octopamine receptor. Messenger RNA expression of AmOctαR1 in different brain neuropils correlates with social task, whereas expression of AmOctβR3/4 changes with age rather than with social role per se. Our results for the first time link the regulatory role of octopamine in division of labour to specific receptors and brain regions. They are an important step forward in our understanding of complex behavioural organization in social groups.     

Combination of fluoxetine and extinction treatments forms a unique synaptic protein profile that correlates with long-term fear reduction in adult mice

The antidepressant fluoxetine induces synaptic plasticity in the visual and fear networks and promotes the structural remodeling of neuronal circuits, which is critical for experience-dependent plasticity in response to an environmental stimulus. We recently demonstrated that chronic fluoxetine administration together with extinction training in adult mice reduced fear in a context-independent manner. Fear conditioning and extinction alter excitatory and inhibitory transmissions within the fear circuitry. In this study, we investigated whether fluoxetine, extinction or their combination produced distinct long-lasting changes in the synaptic protein profile in the amygdala, hippocampus and prefrontal cortex of conditioned mice. We determined that extinction induced synaptophysin expression and down-regulated the GluA1:GluA2 ratio throughout the fear network in water- and fluoxetine-treated mice, suggesting a common fluoxetine-independent mechanism for increased synaptic transmission and re-arrangement of AMPA-receptors by extinction training. In contrast to common changes, the presynaptic vesicular neurotransmitter transporters VGAT and Vglut1 were upregulated after extinction in water- and fluoxetine-treated mice, respectively. The cortical levels of the GABA transporter Gat1 were reduced in high-freezing water-drinking mice, suggesting a maladaptive increase of GABA spillover at cortical inhibitory synapses. Fear conditioning decreased, and extinction induced the expression of GABA-receptor alpha1 and alpha2 subunits in water- and fluoxetine-treated mice, respectively. Only a combination of fluoxetine with extinction enhanced GluN2A expression in the amygdala and hippocampus, emphasizing the role of this NMDA-receptor subunit in the successful erasure of fear memories. Our finding provides novel data that may become helpful in developing beneficial pharmacological fear-reducing treatment strategies.     

d-cycloserine prevents relational memory deficits and suppression of long-term potentiation induced by scopolamine in the hippocampus

Previous research has demonstrated that systemic d-cycloserine (DCS), a partial agonist of the N-methyl-d-aspartate receptor (NMDAR), enhances memory processes in different learning paradigms and attenuates mnemonic deficits produced by diverse pharmacological manipulations. In the present study two experiments were conducted in rats to investigate whether DCS administered in the hippocampus may rescue relational memory deficits and improve deficient synaptic plasticity, both induced by an intracerebral injection of the muscarinic receptor antagonist scopolamine (SCOP). In experiment 1, we assessed whether DCS would prevent SCOP-induced amnesia in an olfactory learning paradigm requiring the integrity of the cholinergic system, the social transmission of food preference (STFP). The results showed that DCS (10 μg/site) injected into the ventral hippocampus (vHPC) before STFP acquisition compensated the 24-h retention deficit elicited by post-training intra-vHPC SCOP (40 μg/site), although it did not affect memory expression in non-SCOP treated rats. In experiment 2, we evaluated whether the perfusion of DCS in hippocampal slices may potentiate synaptic plasticity in CA1 synapses and thus recover SCOP-induced deficits in long-term potentiation (LTP). We found that DCS (50 µM and 100 µM) was able to rescue SCOP (100 µM)-induced LTP maintenance impairment, in agreement with the behavioral findings. Additionally, DCS alone (50 µM and 100 µM) enhanced field excitatory postsynaptic potentials prior to high frequency stimulation, although it did not significantly potentiate LTP. Our results suggest that positive modulation of the NMDAR, by activation of the glycine-binding site, may compensate relational memory impairments due to hippocampal muscarinic neurotransmission dysfunction possibly through enhancements in LTP maintenance.     

Allelic variants in the zinc transporter-3 gene,SLC30A3, a candidate gene identified from gene expression studies,show gender-specific association with schizophrenia

Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both cohorts, SLC30A3, which encodes the Zinc Transporter 3 (ZNT3), is localised to synaptic vesicles in glutamate synapses and known to be involved in cognitive function. In view of the robust depletion of SLC30A3 mRNA in two independent studies and the importance of this gene in cognitive function, we investigated whether single nucleotide polymorphism (SNP) associations with schizophrenia could be detected in a UK case controlled schizophrenia cohort. Four SNPs were selected across this gene and genotyped in a cohort of cases and controls from East UK. We found significant associations with schizophrenia at the allelic (ORs: 1.51 to 1.57), genotype (ORs: 1.46 to 1.53) and haplotype level (P = 2.15 × 10⁻⁴). These associations proved to be gender-specific with significant effects of allele (ORs: 1.74 to 2.11), genotype (ORs: 1.78 to 2.14) and haplotype (P = 3.51 × 10⁻⁵) observed in female schizophrenia cases but not males, when split by gender. In conclusion, SNPs in SLC30A3 showed a gender-specific association with schizophrenia in this East UK cohort, which merits further investigation in other population samples.