Pre- and postsynaptically expressed spike-timing-dependent plasticity contribute differentially to neuronal learning.

A plethora of experimental studies have shown that long-term synaptic plasticity can be expressed pre- or postsynaptically depending on a range of factors such as developmental stage, synapse type, and activity patterns. The functional consequences of this diversity are not clear, although it is understood that whereas postsynaptic expression of plasticity predominantly affects synaptic response amplitude, presynaptic expression alters both synaptic response amplitude and short-term dynamics. In most models of neuronal learning, long-term synaptic plasticity is implemented as changes in connective weights. The consideration of long-term plasticity as a fixed change in amplitude corresponds more closely to post- than to presynaptic expression, which means theoretical outcomes based on this choice of implementation may have a postsynaptic bias. To explore the functional implications of the diversity of expression of long-term synaptic plasticity, we adapted a model of long-term plasticity, more specifically spike-timing-dependent plasticity (STDP), such that it was expressed either independently pre- or postsynaptically, or in a mixture of both ways. We compared pair-based standard STDP models and a biologically tuned triplet STDP model, and investigated the outcomes in a minimal setting, using two different learning schemes: in the first, inputs were triggered at different latencies, and in the second a subset of inputs were temporally correlated. We found that presynaptic changes adjusted the speed of learning, while postsynaptic expression was more efficient at regulating spike timing and frequency. When combining both expression loci, postsynaptic changes amplified the response range, while presynaptic plasticity allowed control over postsynaptic firing rates, potentially providing a form of activity homeostasis. Our findings highlight how the seemingly innocuous choice of implementing synaptic plasticity by single weight modification may unwittingly introduce a postsynaptic bias in modelling outcomes. We conclude that pre- and postsynaptically expressed plasticity are not interchangeable, but enable complimentary functions.

Estimating glomerular filtration rate at the transition from pediatric to adult care.

The current Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend the use of the bedside creatinine-based Chronic Kidney Disease in Children (CKiD) equation to estimate glomerular filtration rate (GFR) in children and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation in adults. However, this approach causes implausible changes in estimated GFR (eGFR) at the transition from pediatric to adult care. We investigated the performance of the KDIGO strategy and various creatinine-based eGFR equations in a cross-sectional dataset of 5,764 subjects (age 10-30 years), using directly measured GFR (mGFR) as reference. We also evaluated longitudinal GFR slopes in 136 subjects who transitioned to adult care. Implausible changes in eGFR resulted from the large overestimation (bias=+21 mL/min/1.73m2) and poor precision of the CKD-EPI equation in the 18-20 year age group, compared to CKiD in the 16-18 year age group (bias=-2.7 mL/min/1.73m2), resulting in a mean change of 23 mL/min/1.73m2 at the transition to adult care. Averaging the CKiD and CKD-EPI estimates in young adults only partially mitigated this issue. The Full Age Spectrum equation (with and without height), the Lund-Malmö Revised equation, and an age-dependent weighted average of CKiD and CKD-EPI resulted in much smaller changes in eGFR at the transition (change of 0.6, -2.1, -0.9 and -1.8 mL/min/1.73m2, respectively). The longitudinal analysis revealed a significant difference in average GFR slope between mGFR and the KDIGO strategy (-2.2 vs. +2.9 mL/min/1.73 m2/year), which was not observed with the other approaches. These results suggest that the KDIGO recommendation for GFR estimation at the pediatric-adult care transition should be revisited.

CosMIC: A Consistent Metric for Spike Inference from Calcium Imaging.

In recent years, the development of algorithms to detect neuronal spiking activity from two-photon calcium imaging data has received much attention, yet few researchers have examined the metrics used to assess the similarity of detected spike trains with the ground truth. We highlight the limitations of the two most commonly used metrics, the spike train correlation and success rate, and propose an alternative, which we refer to as CosMIC. Rather than operating on the true and estimated spike trains directly, the proposed metric assesses the similarity of the pulse trains obtained from convolution of the spike trains with a smoothing pulse. The pulse width, which is derived from the statistics of the imaging data, reflects the temporal tolerance of the metric. The final metric score is the size of the commonalities of the pulse trains as a fraction of their average size. Viewed through the lens of set theory, CosMIC resembles a continuous Sørensen-Dice coefficient-an index commonly used to assess the similarity of discrete, presence/absence data. We demonstrate the ability of the proposed metric to discriminate the precision and recall of spike train estimates. Unlike the spike train correlation, which appears to reward overestimation, the proposed metric score is maximized when the correct number of spikes have been detected. Furthermore, we show that CosMIC is more sensitive to the temporal precision of estimates than the success rate.

GFR estimation based on standardized creatinine and cystatin C: a European multicenter analysis in older adults.

BACKGROUND: Although recommended by the Kidney Disease Improving Global Outcomes, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPICR) creatinine equation was not targeted to estimate glomerular filtration rate (eGFR) among older adults. The Berlin Initiative Study (BIS1CR) equation was specifically developed in older adults, and the Lund-Malmö revised (LMRCR) and the Full Age Spectrum (FASCR) equations have shown promising results in older adults. Our aim was to validate these four creatinine equations, including addition of cystatin C in a large multicenter cohort of Europeans ≥70 years. METHODS: A total of 3226 individuals (2638 with cystatin C) underwent GFR measurement (mGFR; median, 44 mL/min/1.73 m2) using plasma iohexol clearance. Bias, precision (interquartile range [IQR]), accuracy (percent of estimates ±30% of mGFR, P30), eGFR accuracy diagrams and probability diagrams to classify mGFR<45 mL/min/1.73 m2 were compared. RESULTS: The overall results of BIS1CR/CKD-EPICR/FASCR/LMRCR were as follows: median bias, 1.7/3.6/0.6/-0.7 mL/min/1.73 m2; IQR, 11.6/12.3/11.1/10.5 mL/min/1.73 m2; and P30, 77.5%/76.4%/80.9%/83.5% (significantly higher for LMR, p<0.001). Substandard P30 (<75%) was noted for all equations at mGFR<30 mL/min/1.73 m2, and at body mass index values <20 and ≥35 kg/m2. LMRCR had the most stable performance across mGFR subgroups. Only LMRCR and FASCR had a relatively constant small bias across eGFR levels. Probability diagrams exhibited wide eGFR intervals for all equations where mGFR<45 could not be confidently ruled in or out. Adding cystatin C improved P30 accuracy to 85.7/86.8/85.7/88.7 for BIS2CR+CYS/CKD-EPICR+CYS/FASCR+CYS/MEANLMR+CAPA. CONCLUSIONS: LMRCR and FASCR seem to be attractive alternatives to CKD-EPICR in estimating GFR by creatinine-based equations in older Europeans. Addition of cystatin C leads to important improvement in estimation performance.

Measured glomerular filtration rate does not improve prediction of mortality by cystatin C and creatinine.

BACKGROUND: Cystatin C may add explanatory power for associations with mortality in combination with other filtration markers, possibly indicating pathways other than glomerular filtration rate (GFR). However, this has not been firmly established since interpretation of associations independent of measured GFR (mGFR) is limited by potential multicollinearity between markers of GFR. The primary aim of this study was to assess associations between cystatin C and mortality, independent of mGFR. A secondary aim was to evaluate the utility of combining cystatin C and creatinine to predict mortality risk. METHODS: Cox regression was used to assess the associations of cystatin C and creatinine with mortality in 1157 individuals referred for assessment of plasma clearance of iohexol. RESULTS: Since cystatin C and creatinine are inversely related to mGFR, cystatin C - 1 and creatinine - 1 were used. After adjustment for mGFR, lower cystatin C - 1 (higher cystatin C concentration) and higher creatinine - 1 (lower creatinine concentration) were independently associated with increased mortality. When nested models were compared, avoiding the potential influence of multicollinearity, the independence of the associations was supported. Among models combining the markers of GFR, adjusted for demographic factors and comorbidity, cystatin C - 1 and creatinine - 1 combined explained the largest proportion of variance in associations with mortality risk ( R 2 = 0.61). Addition of mGFR did not improve the model. CONCLUSIONS: Our results suggest that both creatinine and cystatin C have independent associations with mortality not explained entirely by mGFR and that mGFR does not offer a more precise mortality risk assessment than these endogenous filtration markers combined.

Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator.

BACKGROUND: Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. METHODS: Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR. RESULTS: We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. CONCLUSIONS: A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

Predictors in adolescence of ESRD in middle-aged men.

BACKGROUND: Identification of predictors of end-stage renal disease (ESRD) in adolescence could provide intervention targets and improve understanding of the cause. STUDY DESIGN: Register-based nested case-control study. SETTING & PARTICIPANTS: A cohort of all Swedish male residents born from 1952 through 1956 who attended mandatory military conscription examinations in late adolescence was used to identify 534 cases and 5,127 controls matched by birth year, county, and vital status. PREDICTOR: Erythrocyte sedimentation rate (ESR), proteinuria, blood pressure, and body mass index (BMI) in late adolescence. OUTCOMES: ESRD (defined here as dialysis therapy, kidney transplantation, surgical procedures creating long-term access for dialysis therapy, or chronic kidney disease stage 5) from 1985 through 2009. MEASUREMENTS: Physical working capacity and cognitive function score in late adolescence. Head of household's occupation and household crowding measured as person-per-room ratio from the 1960 census when participants were children. RESULTS: Proteinuria is associated notably with future ESRD, with an adjusted OR of 7.72 (95% CI, 3.94-15.14; P<0.001) for trace or positive dipstick findings. ESR has a dose-dependent association with ESRD with an adjusted OR of 2.07 (95%CI, 1.14-3.75; P=0.02) for ESR >15mm/h. Hypertension is associated strongly with future ESRD with an OR of 3.97 (95%CI, 2.08-7.59; P<0.001) for grade 2 hypertension and higher. Elevated BMI is associated statistically significantly with increased ESRD risk with an OR of 3.53 (95%CI, 2.04-6.11; P<0.001) for BMI ≥30 compared with 18.5-<25kg/m(2). LIMITATIONS: The study was limited to men, with no initial estimation of glomerular filtration rate, and information on smoking was unavailable. CONCLUSIONS: ESR, proteinuria, BMI, and blood pressure in late adolescence are independent predictors of ESRD in middle-aged men. This highlights the long natural history and importance of adopting a life-course approach when considering the cause of chronic kidney disease.

Structured connectivity in the output of the cerebellar cortex.

The spatial organization of a neuronal circuit is critically important for its function since the location of neurons is often associated with function. In the cerebellum, the major output of the cerebellar cortex are synapses made from Purkinje cells onto neurons in the cerebellar nuclei, yet little has been known about the spatial organization of these synapses. We explored this question using whole-cell electrophysiology and optogenetics in acute sagittal cerebellar slices to produce spatial connectivity maps of cerebellar cortical output in mice. We observed non-random connectivity where Purkinje cell inputs clustered in cerebellar transverse zones: while many nuclear neurons received inputs from a single zone, several multi-zonal connectivity motifs were also observed. Single neurons receiving input from all four zones were overrepresented in our data. These findings reveal that the output of the cerebellar cortex is spatially structured and represents a locus for multimodal integration in the cerebellum.

The developmental profile of visual cortex astrocytes.

We investigated how astrocytes in layer 5 mouse visual cortex mature over postnatal days (P) 3-50. Across this age range, resting membrane potential increased, input resistance decreased, and membrane responses became more passive with age. Two-photon (2p) and confocal imaging of dye-loaded cells revealed that gap-junction coupling increased starting ∼P7. Morphological reconstructions revealed increased branch density but shorter branches after P20, suggesting that astrocyte branches may get pruned as tiling is established. Finally, we visualized spontaneous Ca2+ transients with 2p microscopy and found that Ca2+ events decorrelated, became more frequent and briefer with age. As astrocytes mature, spontaneous Ca2+ activity thus changes from relatively cell-wide, synchronous waves to local transients. Several astrocyte properties were stably mature from ∼P15, coinciding with eye opening, although morphology continued to develop. Our findings provide a descriptive foundation of astrocyte maturation, useful for the study of astrocytic impact on visual cortex critical period plasticity.

Comparing mouse and human brains.

Inhibitory circuit motifs in the mouse brain and the human brain are strikingly similar.

Validation of the Lund-Malmö, Chronic Kidney Disease Epidemiology (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations to estimate glomerular filtration rate in a large Swedish clinical population.

OBJECTIVE: The aim of this study was to validate externally the Swedish Lund-Malmö revised creatinine-based glomerular filtration rate (GFR) equations (LM Revised) in a Swedish cohort in comparison with the North American Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology (CKD-EPI) equations. MATERIAL AND METHODS: The study included 1397 examinations [median age 61 years, median body mass index (BMI) 26 kg/m(2)] in 996 patients referred for iohexol clearance (median 44 ml/min/1.73 m(2)). Bias, precision [interquartile range (IQR)], accuracy expressed as percentage of estimates ± 10% (P(10)) and ± 30% (P(30)) of measured GFR, and classification ability for five GFR stages (<15, 15-29, 30-59, 60-89 and ≥90 ml/min/1.73 m(2)) were compared. RESULTS: Overall, all three equations performed satisfactorily: LM Revised, MDRD, CKD-EPI showed, respectively, a median bias of -5.8%, -2.2% and 1.7%, IQR 11.9, 12.3 and 11.7 ml/min/1.73 m(2), P(10) 35%, 34% and 38%, P(30) 84%, 79% and 79% and correctly classified GFR stages 68%, 65% and 69%. LM Revised was at least as accurate in terms of P(30) as the other equations at GFR intervals <90, while CKD-EPI was the only unbiased and the most accurate equation at ≥90 ml/min/1.73 m(2). LM Revised was more stable in terms of bias and accuracy across age and BMI groups than MDRD and CKD-EPI. Both MDRD and CKD-EPI overestimated measured GFR among elderly patients and in the small group of underweight men. CONCLUSION: The ideal all-purpose GFR prediction equation does not exist. LM Revised should be preferred in patients with suspected or known renal insufficiency, while CKD-EPI is most useful in settings where patients with no a priori suspicion of renal impairment are evaluated. Differences in creatinine measurements between laboratories may limit the generalizability of the present validation.

A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons.

Pyramidal neurons in the cerebral cortex span multiple cortical layers. How the excitable properties of pyramidal neuron dendrites allow these neurons to both integrate activity and store associations between different layers is not well understood, but is thought to rely in part on dendritic backpropagation of action potentials. Here we demonstrate that the sign of synaptic plasticity in neocortical pyramidal neurons is regulated by the spread of the backpropagating action potential to the synapse. This creates a progressive gradient between LTP and LTD as the distance of the synaptic contacts from the soma increases. At distal synapses, cooperative synaptic input or dendritic depolarization can switch plasticity between LTD and LTP by boosting backpropagation of action potentials. This activity-dependent switch provides a mechanism for associative learning across different neocortical layers that process distinct types of information.

Optimal information storage in noisy synapses under resource constraints.

Experimental investigations have revealed that synapses possess interesting and, in some cases, unexpected properties. We propose a theoretical framework that accounts for three of these properties: typical central synapses are noisy, the distribution of synaptic weights among central synapses is wide, and synaptic connectivity between neurons is sparse. We also comment on the possibility that synaptic weights may vary in discrete steps. Our approach is based on maximizing information storage capacity of neural tissue under resource constraints. Based on previous experimental and theoretical work, we use volume as a limited resource and utilize the empirical relationship between volume and synaptic weight. Solutions of our constrained optimization problems are not only consistent with existing experimental measurements but also make nontrivial predictions.

Cystatin C as a filtration marker--haemodialysis patients expose its strengths and limitations.

OBJECTIVE: The reliability of serum cystatin C (s-Cys) as a filtration marker depends on the intra- and inter-individual variation and influence of non-renal factors of its production rate (Cys(pr)), non-renal clearance (CL(nr)) and sieving coefficient (S). Haemodialysis patients with no residual renal function would be the best population in which to investigate these variables, which otherwise require reliable GFR measurements. MATERIAL AND METHODS: Seventy-nine haemodialysis (HD) patients with negligible residual renal function (Group 1) were investigated and compared with 55 HD patients with varying degrees of residual renal function (Group 2) and 923 non-dialysis patients (Group 3). The equation eGFR = Cys(pr)/s-Cys-CL(nr) was used to analyse the turnover and variation of cystatin C. RESULTS: A formula for estimating GFR, eGFR = 99/s-Cys-14.1, calculated from Group 3, was shown to fit the HD patients. The measured s-Cys in Group 1 was 6.9+/-0.9 and 6.4+/-1.1 mg/L in Group 2. The calculated 95% confidence interval of eGFR of +/-(30-40) % increased sharply below GFR 20 mL/min/1.73 m(2), which means that s-Cys cannot be used for calculating low GFR, including the residual GFR of dialysis patients. CONCLUSIONS: Nicotine users in Group 1 had significantly higher s-Cys than non-users (7.5+/-0.9 mg/L compared to 6.7+/-0.8; p = 0.0008), which may be a factor to include in the eGFR formulae. However, s-Cys was independent of non-renal factors such as sex, age, LBM, body weight, malnutrition and CRP and also of changes in CRP.

Novel Optogenetic Approaches in Epilepsy Research.

Epilepsy is a major neurological disorder characterized by repeated seizures afflicting 1% of the global population. The emergence of seizures is associated with several comorbidities and severely decreases the quality of life of patients. Unfortunately, around 30% of patients do not respond to first-line treatment using anti-seizure drugs (ASDs). Furthermore, it is still unclear how seizures arise in the healthy brain. Therefore, it is critical to have well developed models where a causal understanding of epilepsy can be investigated. While the development of seizures has been studied in several animal models, using chemical or electrical induction, deciphering the results of such studies has been difficult due to the uncertainty of the cell population being targeted as well as potential confounds such as brain damage from the procedure itself. Here we describe novel approaches using combinations of optical and genetic methods for studying epileptogenesis. These approaches can circumvent some shortcomings associated with the classical animal models and may thus increase the likelihood of developing new treatment options.

Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors.

There is a consensus that NMDA receptors (NMDARs) detect coincident pre- and postsynaptic activity during induction of long-term potentiation (LTP), but their role in timing-dependent long-term depression (tLTD) is unclear. We examine tLTD in neocortical layer 5 (L5) pyramidal pairs and find that tLTD is expressed presynaptically, implying retrograde signaling. CB1 agonists produce depression that mimics and occludes tLTD. This agonist-induced LTD requires presynaptic activity and NMDAR activation, but not postsynaptic Ca(2+) influx. Further experiments demonstrate the existence of presynaptic NMDARs that underlie the presynaptic activity dependence. Finally, manipulating cannabinoid breakdown alters the temporal window for tLTD. In conclusion, tLTD requires simultaneous activation of presynaptic NMDA and CB1 receptors. This novel form of coincidence detection may explain the temporal window of tLTD and may also impart synapse specificity to cannabinoid retrograde signaling.

Novel presynaptic mechanisms for coincidence detection in synaptic plasticity.

Long-term plasticity typically relies on postsynaptic NMDA receptors to detect the coincidence of pre- and postsynaptic activity. Recent studies, however, have revealed forms of plasticity that depend on coincidence detection by presynaptic NMDA receptors. In the amygdala, cortical afferent associative presynaptic long-term potentiation (LTP) requires activation of presynaptic NMDA receptors by simultaneous thalamic and cortical afferents. Surprisingly, both types of afferent can also undergo postsynaptically induced NMDA-receptor-dependent LTP. In the neocortex, spike-timing-dependent long-term depression (LTD) requires simultaneous activation of presynaptic NMDA autoreceptors and retrograde signalling by endocannabinoids. In cerebellar LTD, presynaptic NMDA receptor activation suggests that similar presynaptic mechanisms may exist. Recent studies also indicate the existence of presynaptic coincidence detection that is independent of NMDA receptors, suggesting that such mechanisms have a widespread role in plasticity.

Highly nonrandom features of synaptic connectivity in local cortical circuits.

How different is local cortical circuitry from a random network? To answer this question, we probed synaptic connections with several hundred simultaneous quadruple whole-cell recordings from layer 5 pyramidal neurons in the rat visual cortex. Analysis of this dataset revealed several nonrandom features in synaptic connectivity. We confirmed previous reports that bidirectional connections are more common than expected in a random network. We found that several highly clustered three-neuron connectivity patterns are overrepresented, suggesting that connections tend to cluster together. We also analyzed synaptic connection strength as defined by the peak excitatory postsynaptic potential amplitude. We found that the distribution of synaptic connection strength differs significantly from the Poisson distribution and can be fitted by a lognormal distribution. Such a distribution has a heavier tail and implies that synaptic weight is concentrated among few synaptic connections. In addition, the strengths of synaptic connections sharing pre- or postsynaptic neurons are correlated, implying that strong connections are even more clustered than the weak ones. Therefore, the local cortical network structure can be viewed as a skeleton of stronger connections in a sea of weaker ones. Such a skeleton is likely to play an important role in network dynamics and should be investigated further.

A proportional but slower NMDA potentiation follows AMPA potentiation in LTP.

Most excitatory glutamatergic synapses contain both AMPA and NMDA receptors, but whether these receptors are regulated together or independently during synaptic plasticity has been controversial. Although long-term potentiation (LTP) is thought to selectively enhance AMPA currents and alter the NMDA-to-AMPA ratio, this ratio is well conserved across synapses onto the same neuron. This suggests that the NMDA-to-AMPA ratio is only transiently perturbed by LTP. To test this, we induced LTP at rat neocortical synapses and recorded mixed AMPA-NMDA currents. We observed rapid LTP of AMPA currents, as well as delayed potentiation of NMDA currents that required previous AMPA potentiation. The delayed potentiation of NMDA currents restored the original NMDA-to-AMPA ratio within 2 h of LTP induction. These data suggest that recruitment of AMPA receptors to synapses eventually induces a proportional increase in NMDA current. This may ensure that LTP does not alter the relative contributions of these two receptors to synaptic transmission and information processing.