STDP in the Developing Sensory Neocortex

Spike timing-dependent plasticity (STDP) has been proposed as a mechanism for optimizing the tuning of neurons to sensory inputs, a process that underlies the formation of receptive field properties and associative memories. The properties of STDP must adjust during development to enable neurons to optimally tune their selectivity for environmental stimuli, but these changes are poorly understood. Here we review the properties of STDP and how these may change during development in primary sensory cortical layers 2/3 and 4, initial sites for intracortical processing. We provide a primer discussing postnatal developmental changes in synaptic proteins and neuromodulators that are thought to influence STDP induction and expression. We propose that STDP is shaped by, but also modifies, synapses to produce refinements in neuronal responses to sensory inputs

Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity

NMDA-type glutamate receptors (NMDARs) mediate many forms of synaptic plasticity. These tetrameric receptors consist of two obligatory NR1 subunits and two regulatory subunits, usually a combination of NR2A and NR2B. In the neonatal neocortex NR2B-containing NMDARs predominate, and sensory experience facilitates a developmental switch in which NR2A levels increase relative to NR2B. In this review, we clarify the roles of NR2 subunits in synaptic plasticity, and argue that a primary role of this shift is to control the threshold, rather than determining the direction, for modifying synaptic strength. We also discuss recent studies that illuminate the mechanisms regulating NR2 subunits, and suggest that the NR2A/NR2B ratio is regulated by multiple means, which may control the ratio both locally at individual synapses and globally in a cell-wide manner. Finally, we use the visual cortex as a model system to illustrate how activity-dependent modifications in the NR2A/NR2B ratio may contribute to the development of cortical functions

Roles of Presynaptic NMDA Receptors in Neurotransmission and Plasticity

Presynaptic NMDA receptors (preNMDARs) play pivotal roles in excitatory neurotransmission and synaptic plasticity. They facilitate presynaptic neurotransmitter release and modulate mechanisms controlling synaptic maturation and plasticity during formative periods of brain development. There is an increasing understanding of the roles of preNMDARs in experience-dependent synaptic and circuit-specific computation. In this review, we summarize the latest understanding of compartment-specific expression and function of preNMDARs, and how they contribute to synapse-specific and circuit-level information processing

Glycine Receptors Support Excitatory Neurotransmitter Release in Developing Mouse Visual Cortex.

Glycine receptors (GlyRs) are found in most areas of the brain, and their dysfunction can cause severe neurological disorders. While traditionally thought of as inhibitory receptors, presynaptic-acting GlyRs (preGlyRs) can also facilitate glutamate release under certain circumstances, although the underlying molecular mechanisms are unknown. In the current study, we sought to better understand the role of GlyRs in the facilitation of excitatory neurotransmitter release in mouse visual cortex. Using whole-cell recordings, we found that preGlyRs facilitate glutamate release in developing, but not adult, visual cortex. The glycinergic enhancement of neurotransmitter release in early development depends on the high intracellular to extracellular Cl(-) gradient maintained by the Na(+)-K(+)-2Cl(-) cotransporter and requires Ca(2+) entry through voltage-gated Ca(2+) channels. The glycine transporter 1, localized to glial cells, regulates extracellular glycine concentration and the activation of these preGlyRs. Our findings demonstrate a developmentally regulated mechanism for controlling excitatory neurotransmitter release in the neocortex

Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice

Mutations or deletions of the maternal allele of the UBE3A gene cause Angelman syndrome (AS), a severe neurodevelopmental disorder. The paternal UBE3A/Ube3a allele becomes epigenetically silenced in most neurons during postnatal development in humans and mice; hence, loss of the maternal allele largely eliminates neuronal expression of UBE3A protein. However, recent studies suggest that paternal Ube3a may escape silencing in certain neuron populations, allowing for persistent expression of paternal UBE3A protein. Here we extend evidence in AS model mice (Ube3am–/p+) of paternal UBE3A expression within the suprachiasmatic nucleus (SCN), the master circadian pacemaker. Paternal UBE3A-positive cells in the SCN show partial colocalization with the neuropeptide arginine vasopressin (AVP) and clock proteins (PER2 and BMAL1), supporting that paternal UBE3A expression in the SCN is often of neuronal origin. Paternal UBE3A also partially colocalizes with a marker of neural progenitors, SOX2, implying that relaxed or incomplete imprinting of paternal Ube3a reflects an overall immature molecular phenotype. Our findings highlight the complexity of Ube3a imprinting in the brain and illuminate a subpopulation of SCN neurons as a focal point for future studies aimed at understanding the mechanisms of Ube3a imprinting

Subcellular organization of UBE3A in human cerebral cortex.

BackgroundLoss of UBE3A causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism. Despite this powerful association with neurodevelopmental disorders, there is still much to be learned about UBE3A, including its cellular and subcellular organization in the human brain. The issue is important, since UBE3A's localization is integral to its function.MethodsWe used light and electron microscopic immunohistochemistry to study the cellular and subcellular distribution of UBE3A in the adult human cerebral cortex. Experiments were performed on multiple tissue sources, but our results focused on optimally preserved material, using surgically resected human temporal cortex of high ultrastructural quality from nine individuals.ResultsWe demonstrate that UBE3A is expressed in both glutamatergic and GABAergic neurons, and to a lesser extent in glial cells. We find that UBE3A in neurons has a non-uniform subcellular distribution. In somata, UBE3A preferentially concentrates in euchromatin-rich domains within the nucleus. Electron microscopy reveals that labeling concentrates in the head and neck of dendritic spines and is excluded from the PSD. Strongest labeling within the neuropil was found in axon terminals.ConclusionsBy highlighting the subcellular compartments in which UBE3A is likely to function in the human neocortex, our data provide insight into the diverse functional capacities of this E3 ligase. These anatomical data may help to elucidate the role of UBE3A in Angelman syndrome and autism spectrum disorder

Visual Deprivation Modifies Both Presynaptic Glutamate Release and the Composition of Perisynaptic/Extrasynaptic NMDA Receptors in Adult Visual Cortex

Use-dependent modifications of synapses have been well described in the developing visual cortex, but the ability for experience to modify synapses in the adult visual cortex is poorly understood. We found that 10 d of late-onset visual deprivation modifies both presynaptic and postsynaptic elements at the layer 4-->2/3 connection in the visual cortex of adult mice, and these changes differ from those observed in juveniles. Although visual deprivation in juvenile mice modifies the subunit composition and increases the current duration of synaptic NMDA receptors (NMDARs), no such effect is observed at synapses between layer 4 and layer 2/3 pyramidal neurons in adult mice. Surprisingly, visual deprivation in adult mice enhances the temporal summation of NMDAR-mediated currents induced by bursts of high-frequency stimulation. The enhanced temporal summation of NMDAR-mediated currents in deprived cortex could not be explained by a reduction in the rate of synaptic depression, because our data indicate that late-onset visual deprivation actually increases the rate of synaptic depression. Biochemical and electrophysiological evidence instead suggest that the enhanced temporal summation in adult mice could be accounted for by a change in the molecular composition of NMDARs at perisynaptic/extrasynaptic sites. Our data demonstrate that the experience-dependent modifications observed in the adult visual cortex are different from those observed during development. These differences may help to explain the unique consequences of sensory deprivation on plasticity in the developing versus mature cortex

Addressing evidence treatment gaps for cardiovascular disease through primary care collaboration

Aims &amp; Rationale/ObjectivesThe aim is to establish the frequency of counselling by general practitioners (GPs) and community pharmacists (CPs) for patients with uncontrolled CVD risk factors. This will identify conditions for which CPs might collaborate with GPs in addressing evidence-treatment gaps.MethodsA population survey undertaken in the Wimmera region of Victoria in 2006. 1425 adults aged 25-84 yrs were randomly selected using age/sex stratified electoral role samples. A representative 723 participants were recruited.Principal FindingsData on GP and CP visits were available for 694 participants. Overall, participants visited GPs 4.6 times and CPs 6.0 times/annum. However, one third of participants never consulted a pharmacist in 12 months compared to just 11.5% for GPs. Among obese patients (BMI ?? 30), the average number of visits/annum was 4.5 to GPs and 6.8 to CPs. The equivalent numbers were 5.6 and 8.6 respectively for those with systolic BP ?? 140 mmHg; 3.7 and 5.5 for total cholesterol &gt; 5.0 mmol/L; and, 6.7 and 14.6 for patients with random blood glucose concentrations ?? 7.0 mmol/L.ImplicationsPeople with suboptimal status for most common CVD risk factor are counselled frequently by CPs. A coordinated approach with GPs to the delivery of cardiovascular health promotion could provide valuable reinforcement of key messages and offers greater opportunity to identify at-risk individuals. Acknowledgements: KM is a pharmacist-academic at Greater Green Triangle UDRH, a position funded by the Department of Health and Ageing through the Rural and Remote Pharmacy Workforce Development Program<br /