Conventional measures of intrinsic excitability are poor estimators of neuronal activity under realistic synaptic inputs

Activity-dependent regulation of intrinsic excitability has been shown to greatly contribute to the overall plasticity of neuronal circuits. Such neuroadaptations are commonly investigated in patch clamp experiments using current step stimulation and the resulting input-output functions are analyzed to quantify alterations in intrinsic excitability. However, it is rarely addressed, how such changes translate to the function of neurons when they operate under natural synaptic inputs. Still, it is reasonable to expect that a strong correlation and near proportional relationship exist between static firing responses and those evoked by synaptic drive. We challenge this view by performing a high-yield electrophysiological analysis of cultured mouse hippocampal neurons using both standard protocols and simulated synaptic inputs via dynamic clamp. We find that under these conditions the neurons exhibit vastly different firing responses with surprisingly weak correlation between static and dynamic firing intensities. These contrasting responses are regulated by two intrinsic K-currents mediated by Kv1 and Kir channels, respectively. Pharmacological manipulation of the K-currents produces differential regulation of the firing output of neurons. Static firing responses are greatly increased in stuttering type neurons under blocking their Kv1 channels, while the synaptic responses of the same neurons are less affected. Pharmacological blocking of Kir-channels in delayed firing type neurons, on the other hand, exhibit the opposite effects. Our subsequent computational model simulations confirm the findings in the electrophysiological experiments and also show that adaptive changes in the kinetic properties of such currents can even produce paradoxical regulation of the firing output.

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Regulation of intrinsic excitability in hippocampal neurons by activity-dependent modulation of the KV2.1 potassium channel

Channels ◽

10.4161/chan.3.1.7655 ◽

2009 ◽

Vol 3 (1) ◽

pp. 46-56 ◽

Cited By ~ 53

Author(s):

Durga P. Mohapatra ◽

Hiroaki Misonou ◽

Pan Sheng-Jun ◽

Joshua E. Held ◽

D. James Surmeier ◽

...

Keyword(s):

Potassium Channel ◽

Hippocampal Neurons ◽

Intrinsic Excitability ◽

Activity Dependent

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Dynamic-Clamp Analysis of the Effects of Convergence on Spike Timing. I. Many Synaptic Inputs

Journal of Neurophysiology ◽

10.1152/jn.01307.2004 ◽

2005 ◽

Vol 94 (4) ◽

pp. 2512-2525 ◽

Cited By ~ 23

Author(s):

Matthew A. Xu-Friedman ◽

Wade G. Regehr

Keyword(s):

Spike Timing ◽

Synaptic Conductance ◽

Dynamic Clamp ◽

Synaptic Inputs ◽

Timing Variability ◽

Large N ◽

Auditory Brain Stem ◽

Sensory Acuity ◽

Activity Dependent

Precise action potential timing is crucial in sensory acuity and motor control. Convergence of many synaptic inputs is thought to provide a means of decreasing spike-timing variability (“jitter”), but its effectiveness has never been tested in real neurons. We used the dynamic-clamp technique in mouse auditory brain stem slices to examine how convergence controls spike timing. We tested the roles of several synaptic properties that are influenced by ongoing activity in vivo: the number of active inputs ( N), their total synaptic conductance ( Gtot), and their timing, which can resemble an alpha or a Gaussian distribution. Jitter was reduced most with large N, up to a factor of over 20. Variability in N is likely to occur in vivo, but this added little jitter. Jitter reduction also depended on the timing of inputs: alpha-distributed inputs were more effective than Gaussian-distributed inputs. Furthermore, the two distributions differed in their sensitivity to synaptic conductance: for Gaussian-distributed inputs, jitter was most reduced when Gtot was 2–3 times threshold, whereas alpha-distributed inputs showed continued jitter reduction with higher Gtot. However, very high Gtot caused the postsynaptic cell to fire multiple times, particularly when the input jitter outlasted the cell's refractory period, which interfered with jitter reduction. Gtot also greatly affected the response latency, which could influence downstream computations. Changes in Gtot are likely to arise in vivo through activity-dependent changes in synaptic strength. High rates of postsynaptic activity increased the number of synaptic inputs required to evoke a postsynaptic response. Despite this, jitter was still effectively reduced, particularly in cases when this increased threshold eliminated secondary spikes. Thus these studies provide insight into how specific features of converging inputs control spike timing.

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Translocation of CaMKII to dendritic microtubules supports the plasticity of local synapses

The Journal of Cell Biology ◽

10.1083/jcb.201202058 ◽

2012 ◽

Vol 198 (6) ◽

pp. 1055-1073 ◽

Cited By ~ 50

Author(s):

Mado Lemieux ◽

Simon Labrecque ◽

Christian Tardif ◽

Étienne Labrie-Dion ◽

Éric LeBel ◽

...

Keyword(s):

Synaptic Plasticity ◽

Protein Kinase ◽

Hippocampal Neurons ◽

Synaptic Development ◽

Dependent Protein Kinase ◽

Synaptic Inputs ◽

Downstream Signaling ◽

Dependent Protein ◽

Activity Dependent ◽

Cultured Hippocampal Neurons

The processing of excitatory synaptic inputs involves compartmentalized dendritic Ca2+ oscillations. The downstream signaling evoked by these local Ca2+ transients and their impact on local synaptic development and remodeling are unknown. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an important decoder of Ca2+ signals and mediator of synaptic plasticity. In addition to its known accumulation at spines, we observed with live imaging the dynamic recruitment of CaMKII to dendritic subdomains adjacent to activated synapses in cultured hippocampal neurons. This localized and transient enrichment of CaMKII to dendritic sites coincided spatially and temporally with dendritic Ca2+ transients. We show that it involved an interaction with microtubular elements, required activation of the kinase, and led to localized dendritic CaMKII autophosphorylation. This process was accompanied by the adjacent remodeling of spines and synaptic AMPA receptor insertion. Replacement of endogenous CaMKII with a mutant that cannot translocate within dendrites lessened this activity-dependent synaptic plasticity. Thus, CaMKII could decode compartmental dendritic Ca2+ transients to support remodeling of local synapses.

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Faculty Opinions recommendation of Bidirectional activity-dependent morphological plasticity in hippocampal neurons.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1022832.264708 ◽

2004 ◽

Author(s):

Michael Ehlers

Keyword(s):

Hippocampal Neurons ◽

Morphological Plasticity ◽

Activity Dependent

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Effects of neuronal proteoglycans on activity-dependent growth responses of fetal hippocampal neurons

Molecular Brain Research ◽

10.1016/s0169-328x(97)00111-3 ◽

1997 ◽

Vol 48 (2) ◽

pp. 355-366 ◽

Cited By ~ 3

Author(s):

Wei Wang ◽

Kimberly E Dow

Keyword(s):

Hippocampal Neurons ◽

Growth Responses ◽

Dependent Growth ◽

Activity Dependent

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Differential Oxidative Modulation of Voltage-Dependent K+ Currents in Rat Hippocampal Neurons

Journal of Neurophysiology ◽

10.1152/jn.2002.87.6.2990 ◽

2002 ◽

Vol 87 (6) ◽

pp. 2990-2995 ◽

Cited By ~ 42

Author(s):

Wolfgang Müller ◽

Katrin Bittner

Keyword(s):

Hydrogen Peroxide ◽

Hippocampal Neurons ◽

Immune Defense ◽

Delayed Rectifier ◽

Delayed Rectifier Current ◽

Cell Recording ◽

Voltage Dependent ◽

Steady State Inactivation ◽

K Currents ◽

Stimulation Of

Oxidative stress is enhanced by [Ca2+]i-dependent stimulation of phospholipases and mitochondria and has been implicated in immune defense, ischemia, and excitotoxicity. Using whole cell recording from hippocampal neurons, we show that arachidonic acid (AA) and hydrogen peroxide (H2O2) both reduce the transient K+ current I A by −54 and −68%, respectively, and shift steady-state inactivation by −10 and −15 mV, respectively. While AA was effective at an extracellular concentration of 1 μM and an intracellular concentration of 1 pM, extracellular H2O2 was equally effective only at a concentration >800 μM (0.0027%). In contrast to AA, H2O2 decreased the slope of activation and increased the slope of inactivation of I A and reduced the sustained delayed rectifier current I K(V) by 22% and shifted its activation by −9 mV. Intracellular application of the antioxidant glutathione (GSH, 2–5 mM) blocked all effects of AA and the reduction of I A by H2O2. In contrast, intracellular GSH enhanced reduction of I K(V) by H2O2. Decrease of the slope of activation and increase of the slope of inactivation of I A by hydrogen peroxide was blocked and reversed to a decrease, respectively, by intracellular application of GSH. Intracellular GSH did not prevent H2O2 to shift inactivation and activation of I A and activation of I K(V) to more negative potentials. We conclude, that AA and H2O2modulate voltage-activated K currents differentially by oxidation of GSH accessible intracellular and GSH inaccessible extracellular K+-channel domains, thereby presumably affecting neuronal information processing and oxidative damage.

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Dynamics of Excitatory Transmitter Release: Analysis of Synaptic Responses in CA3 Hippocampal Neurons After Repetitive Stimulation of Afferent Fibers

Journal of Neurophysiology ◽

10.1152/jn.1998.79.4.1977 ◽

1998 ◽

Vol 79 (4) ◽

pp. 1977-1988 ◽

Cited By ~ 15

Author(s):

Marco Canepari ◽

Enrico Cherubini

Keyword(s):

Transmitter Release ◽

Hippocampal Neurons ◽

Repetitive Stimulation ◽

Patch Clamp Technique ◽

Afferent Fibers ◽

Presynaptic Mechanisms ◽

Release Analysis ◽

Excitatory Transmitter ◽

Stimulation Of ◽

Synaptic Responses

Canepari, Marco and Enrico Cherubini. Dynamics of excitatory transmitter release: analysis of synaptic responses in CA3 hippocampal neurons after repetitive stimulation of afferent fibers. J. Neurophysiol. 79: 1977–1988, 1998. The patch-clamp technique (whole cell configuration) was used to record excitatory postsynaptic currents (EPSCs) evoked by repetitive stimulation (4 pulses at 50-ms intervals) of afferent fibers in the stratum lucidum-radiatum. Different synaptic behaviors (EPSC patterns) were classified in terms of facilitation or depression of the mean amplitude of the second, third, and fourth EPSC with respect to the previous one. A large variety of EPSC patterns was observed by stimulating different afferent fibers. Experiments with the mGluR2/mGluR3 agonist 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) (1 μM), a compound that reduces release at mossy but not at associative commissural fibers and therefore allows to identify the origin of synaptic responses, showed that particular EPSC patterns could not be associated to the activation of a specific type of synaptic input. To investigate the role of the probability of release in the dynamics of synaptic activity, the extracellular calcium concentration was varied from 0.8 to 4 mM in several experiments. EPSC patterns dominated by depression, characteristics of high release probability conditions, could be observed in the majority of the cases in the presence of higher calcium concentrations. A quantitative model for dynamics of transmitter release has been developed. Experimental results were compared with data computed with the model taking into account the probability of release and the time course of reavailability. This work indicates that short-term changes of presynaptic conditions occurring during a train of action potentials can account for the high variability of EPSC responses. The model that is proposed also suggests a general method of experimental data analysis to investigate the possible presynaptic mechanisms underlying long-lasting changes in synaptic efficacy.

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Staggered Development of GABAergic and Glycinergic Transmission in the MNTB

Journal of Neurophysiology ◽

10.1152/jn.00798.2004 ◽

2005 ◽

Vol 93 (2) ◽

pp. 819-828 ◽

Cited By ~ 85

Author(s):

Gautam B. Awatramani ◽

Rostislav Turecek ◽

Laurence O. Trussell

Keyword(s):

Decay Rate ◽

Release Kinetics ◽

Vesicle Release ◽

Synaptic Inputs ◽

Postsynaptic Currents ◽

Medial Nucleus ◽

Immature Rats ◽

Fast Kinetic ◽

Trapezoid Body ◽

Synaptic Responses

Maturation of some brain stem and spinal inhibitory systems is characterized by a shift from GABAergic to glycinergic transmission. Little is known about how this transition is expressed in terms of individual axonal inputs and synaptic sites. We have explored this issue in the rat medial nucleus of the trapezoid body (MNTB). Synaptic responses at postnatal days 5–7 (P5–P7) were small, slow, and primarily mediated by GABAA receptors. By P8–P12, an additional, faster glycinergic component emerged. At these ages, GABAA, glycine, or both types of receptors mediated transmission, even at single synaptic sites. Thereafter, glycinergic development greatly accelerated. By P25, evoked inhibitory postsynaptic currents (IPSCs) were 10 times briefer and 100 times larger than those measured in the youngest group, suggesting a proliferation of synaptic inputs activating fast-kinetic receptors. Glycinergic miniature IPSCs (mIPSCs) increased markedly in size and decay rate with age. GABAergic mIPSCs also accelerated, but declined slightly in amplitude. Overall, the efficacy of GABAergic inputs showed little maturation between P5 and P20. Although gramicidin perforated-patch recordings revealed that GABA or glycine depolarized P5–P7 cells but hyperpolarized P14–P15 cells, the young depolarizing inputs were not suprathreshold. In addition, vesicle-release properties of inhibitory axons also matured: GABAergic responses in immature rats were highly asynchronous, while in older rats, precise, phasic glycinergic IPSCs could transmit even with 500-Hz stimuli. Thus development of inhibition is characterized by coordinated modifications to transmitter systems, vesicle release kinetics, Cl− gradients, receptor properties, and numbers of synaptic inputs. The apparent switch in GABA/glycine transmission was predominantly due to enhanced glycinergic function.

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