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1.  Investigating mechanisms underlying neurodevelopmental phenotypes of autistic and intellectual disability disorders: a perspective 
Brain function and behavior undergo significant plasticity and refinement, particularly during specific critical and sensitive periods. In autistic and intellectual disability (ID) neurodevelopmental disorders (NDDs) and their corresponding genetic mouse models, impairments in many neuronal and behavioral phenotypes are temporally regulated and in some cases, transient. However, the links between neurobiological mechanisms governing typically normal brain and behavioral development (referred to also as “neurotypical” development) and timing of NDD impairments are not fully investigated. This perspective highlights temporal patterns of synaptic and neuronal impairment, with a restricted focus on autism and ID types of NDDs. Given the varying known genetic and environmental causes for NDDs, this perspective proposes two strategies for investigation: (1) a focus on neurobiological mechanisms underlying known critical periods in the (typically) normal-developing brain; (2) investigation of spatio-temporal expression profiles of genes implicated in monogenic syndromes throughout affected brain regions. This approach may help explain why many NDDs with differing genetic causes can result in overlapping phenotypes at similar developmental stages and better predict vulnerable periods within these disorders, with implications for both therapeutic rescue and ultimately, prevention.
doi:10.3389/fnsys.2013.00075
PMCID: PMC3814085  PMID: 24198768
neurodevelopmental disorders; critical periods; gene expression; phenotype; development
2.  STDP and Mental Retardation: Dysregulation of Dendritic Excitability in Fragile X Syndrome 
Development of cognitive function requires the formation and refinement of synaptic networks of neurons in the brain. Morphological abnormalities of synaptic spines occur throughout the brain in a wide variety of syndromic and non-syndromic disorders of mental retardation (MR). In both neurons from human post-mortem tissue and mouse models of retardation, the changes observed in synaptic spine and dendritic morphology can be subtle, in the range of 10–20% alterations for spine protrusion length and density. Functionally, synapses in hippocampus and cortex show deficits in long-term potentiation (LTP) and long-term depression (LTD) in an array of neurodevelopmental disorders including Down's, Angelman, Fragile X and Rett syndrome. Recent studies have shown that in principle the machinery for synaptic plasticity is in place in these synapses, but that significant alterations in spike-timing-dependent plasticity (STDP) induction rules exist in cortical synaptic pathways of Fragile X MR syndrome. In this model, the threshold for inducing timing-dependent long-term potentiation (tLTP) is increased in these synapses. Increased postsynaptic activity can overcome this threshold and induce normal levels of tLTP. In this review, we bring together recent studies investigating STDP in neurodevelopmental learning disorders using Fragile X syndrome as a model and we argue that alterations in dendritic excitability underlie deficits seen in STDP. Known and candidate dendritic mechanisms that may underlie the plasticity deficits are discussed. Studying STDP in monogenic MR syndromes with clear deficits in information processing at the cognitive level also provides the field with an opportunity to make direct links between cognition and processing rules at the synapse during development.
doi:10.3389/fnsyn.2010.00010
PMCID: PMC3059693  PMID: 21423496
STDP; mental retardation; Fragile X syndrome; LTP; dendritic excitability; calcium; spine; dendrite
3.  Hyperconnectivity and Slow Synapses during Early Development of Medial Prefrontal Cortex in a Mouse Model for Mental Retardation and Autism 
Neuronal theories of neurodevelopmental disorders (NDDs) of autism and mental retardation propose that abnormal connectivity underlies deficits in attentional processing. We tested this theory by studying unitary synaptic connections between layer 5 pyramidal neurons within medial prefrontal cortex (mPFC) networks in the Fmr1-KO mouse model for mental retardation and autism. In line with predictions from neurocognitive theory, we found that neighboring pyramidal neurons were hyperconnected during a critical period in early mPFC development. Surprisingly, excitatory synaptic connections between Fmr1-KO pyramidal neurons were significantly slower and failed to recover from short-term depression as quickly as wild type (WT) synapses. By 4--5 weeks of mPFC development, connectivity rates were identical for both KO and WT pyramidal neurons and synapse dynamics changed from depressing to facilitating responses with similar properties in both groups. We propose that the early alteration in connectivity and synaptic recovery are tightly linked: using a network model, we show that slower synapses are essential to counterbalance hyperconnectivity in order to maintain a dynamic range of excitatory activity. However, the slow synaptic time constants induce decreased responsiveness to low-frequency stimulation, which may explain deficits in integration and early information processing in attentional neuronal networks in NDDs.
doi:10.1093/cercor/bhr224
PMCID: PMC3561643  PMID: 21856714
autism; EPSC; Fragile X; hyperconnectivity; prefrontal cortex
4.  Layer-specific high-frequency action potential spiking in the prefrontal cortex of awake rats 
Cortical pyramidal neurons show irregular in vivo action potential (AP) spiking with high-frequency bursts occurring on sparse background activity. Somatic APs can backpropagate from soma into basal and apical dendrites and locally generate dendritic calcium spikes. The critical AP frequency for generation of such dendritic calcium spikes can be very different depending on cell type or brain area involved. Previously, it was shown in vitro that calcium electrogenesis can be induced in L(ayer) 5 pyramidal neurons of prefrontal cortex (PFC). It remains an open question whether somatic burst spiking and the resulting dendritic calcium electrogenesis also occur in morphologically more compact L2/3 pyramidal neurons. Furthermore, it is not known whether critical frequencies that trigger dendritic calcium electrogenesis occur in PFC under awake conditions in vivo. Here, we addressed these issues and found that pyramidal neurons in both PFC L2/3 and L5 in awake rats spike APs in short bursts but with different probabilities. The critical frequency (CF) for calcium electrogenesis in vitro was layer-specific and lower in L5 neurons compared to L2/3. Taking the in vitro CF as a predictive measure for dendritic electrogenesis during in vivo spontaneous activity, supracritical bursts in vivo were observed in a larger fraction of L5 neurons compared to L2/3 neurons but with similar incidence within these subpopulations. Together, these results show that in PFC of awake rats, AP spiking occurs at frequencies that are relevant for dendritic calcium electrogenesis and suggest that in awake rat PFC, dendritic calcium electrogenesis may be involved in neuronal computation.
doi:10.3389/fncel.2013.00099
PMCID: PMC3693071  PMID: 23805075
calcium electrogenesis; prefrontal cortex; action potential; high-frequency bursts; dendrites; backpropagation; in vivo; awake rats
5.  Spine Calcium Transients Induced by Synaptically-Evoked Action Potentials Can Predict Synapse Location and Establish Synaptic Democracy 
PLoS Computational Biology  2012;8(6):e1002545.
CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called “synaptic democracy”. How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy.
Author Summary
Neurons receive information from other neurons via hundreds of contacts (synapses) spread across their dendritic branches. Input signals from synapses propagate along a dendrite to the cell body (soma), where the neuron decides whether or not to produce an action potential. Signals that travel further decay more. Were all synapses equally strong, a synapse far from the soma would have less influence on the decision than a synapse close by. However, neurons in the hippocampus, which are involved in learning and memory, have synapses far from the soma that are stronger than those close by, so that all synapses have an equal voice (“synaptic democracy”). But how can a synapse “know” how far it is from the soma? Using a computational model of a hippocampal neuron, we show that the action potential, which propagates from the soma back into the dendrites, contains information with which synapses can estimate their somatic distance. Specifically, the calcium concentration at the synapse, which is modulated by the backpropagating action potential, decreases with distance from the soma. We show that when the strength of a synapse is adapted in a self-organising manner based on calcium concentration, synaptic democracy is obtained.
doi:10.1371/journal.pcbi.1002545
PMCID: PMC3375220  PMID: 22719238
6.  Double Dissociation of Spike Timing–Dependent Potentiation and Depression by Subunit-Preferring NMDA Receptor Antagonists in Mouse Barrel Cortex 
Cerebral Cortex (New York, NY)  2009;19(12):2959-2969.
Spike timing–dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation (t-LTP) requires postsynaptic NMDA receptors, timing-dependent long-term depression (t-LTD) requires the activation of presynaptic NMDA receptors at layer 4-to-layer 2/3 synapses in barrel cortex. Here we investigated the developmental profile of t-LTD at layer 4-to-layer 2/3 synapses of mouse barrel cortex and studied their NMDA receptor subunit dependence. Timing-dependent LTD emerged in the first postnatal week, was present during the second week and disappeared in the adult, whereas t-LTP persisted in adulthood. An antagonist at GluN2C/D subunit–containing NMDA receptors blocked t-LTD but not t-LTP. Conversely, a GluN2A subunit–preferring antagonist blocked t-LTP but not t-LTD. The GluN2C/D subunit requirement for t-LTD appears to be synapse specific, as GluN2C/D antagonists did not block t-LTD at horizontal cross-columnar layer 2/3-to-layer 2/3 synapses, which was blocked by a GluN2B antagonist instead. These data demonstrate an NMDA receptor subunit-dependent double dissociation of t-LTD and t-LTP mechanisms at layer 4-to-layer 2/3 synapses, and suggest that t-LTD is mediated by distinct molecular mechanisms at different synapses on the same postsynaptic neuron.
doi:10.1093/cercor/bhp067
PMCID: PMC2774397  PMID: 19363149
development; LTD; LTP; rodent; synaptic plasticity
7.  High Speed Two-Photon Imaging of Calcium Dynamics in Dendritic Spines: Consequences for Spine Calcium Kinetics and Buffer Capacity 
PLoS ONE  2007;2(10):e1073.
Rapid calcium concentration changes in postsynaptic structures are crucial for synaptic plasticity. Thus far, the determinants of postsynaptic calcium dynamics have been studied predominantly based on the decay kinetics of calcium transients. Calcium rise times in spines in response to single action potentials (AP) are almost never measured due to technical limitations, but they could be crucial for synaptic plasticity. With high-speed, precisely-targeted, two-photon point imaging we measured both calcium rise and decay kinetics in spines and secondary dendrites in neocortical pyramidal neurons. We found that both rise and decay kinetics of changes in calcium-indicator fluorescence are about twice as fast in spines. During AP trains, spine calcium changes follow each AP, but not in dendrites. Apart from the higher surface-to-volume ratio (SVR), we observed that neocortical dendritic spines have a markedly smaller endogenous buffer capacity with respect to their parental dendrites. Calcium influx time course and calcium extrusion rate were both in the same range for spines and dendrites when fitted with a dynamic multi-compartment model that included calcium binding kinetics and diffusion. In a subsequent analysis we used this model to investigate which parameters are critical determinants in spine calcium dynamics. The model confirmed the experimental findings: a higher SVR is not sufficient by itself to explain the faster rise time kinetics in spines, but only when paired with a lower buffer capacity in spines. Simulations at zero calcium-dye conditions show that calmodulin is more efficiently activated in spines, which indicates that spine morphology and buffering conditions in neocortical spines favor synaptic plasticity.
doi:10.1371/journal.pone.0001073
PMCID: PMC2034355  PMID: 17957255

Results 1-7 (7)