Excitatory Postsynaptic Conductances Research Articles

Genetic Variant in GRM1 Underlies Congenital Cerebellar Ataxia with No Obvious Intellectual Disability.

Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The GRM1 gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the GRM1 gene have previously been known to cause autosomal recessive and autosomal dominant spinocerebellar ataxias. In this study, whole-exome sequencing of a patient from a family of Azerbaijani origin with a diagnosis of congenital cerebellar ataxia was performed, and a new homozygous missense mutation in the GRM1 gene was identified. The mutation leads to the homozygous amino acid substitution of p.Thr824Arg in an evolutionarily highly conserved region encoding the transmembrane domain 7, which is critical for ligand binding and modulating of receptor activity. This is the first report in which a mutation has been identified in the last transmembrane domain of the mGluR1, causing a congenital autosomal recessive form of cerebellar ataxia with no obvious intellectual disability. Additionally, we summarized all known presumable pathogenic genetic variants in the GRM1 gene to date. We demonstrated that multiple rare variants in the GRM1 underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation.

Synaptic plasticity investigation in permalloy based channel material for neuromorphic computing

Artificial synaptic devices capable of synchronized storing and processing of information are the critical building blocks of neuromorphic computing systems for the low-power implementation of artificial intelligence. Compared to the diverse synaptic device structures, the emerging electrolyte-gated synaptic transistors are promising for mimicking biological synapses owing to their analogous working mode. Despite the remarkable progress in electrolyte-gated synaptic transistors, the study of metallic channel-based synaptic devices remains vastly unexplored. Here, we report a three-terminal electrolyte-gated artificial synapse based on metallic permalloy as the active layer. Gating controlled, non-volatile, rewritable, and distinct multilevel conductance states have been achieved for analog computing. Representative synaptic behaviors such as excitatory postsynaptic conductance, paired-pulse facilitation, spike amplitude-dependent plasticity, spike duration-dependent plasticity, and long-term potentiation/depression have been successfully simulated in the synaptic device. Furthermore, switching from short-term to long-term memory regimes has been demonstrated through repeated training. Benefitting from the short-term facilitation, the synaptic device can also act as a high-pass temporal filter for selective communication. This research highlights the great potential of metallic channel-based synaptic devices for future neuromorphic systems and augments the diversity of synaptic devices.

Effects of Ethanol on Synaptic Plasticity and NMDA Currents in the Juvenile Rat Dentate Gyrus

Background and Objectives:We examined how acute ethanol (EtOH) exposure affects long term depression (LTD) in the dentate gyrus (DG) of the hippocampus in juvenile rats. EtOH is thought to directly modulate n-methyl-D-aspartate receptor (NMDAr) currents, which are believed important for LTD induction. LTD in turn is believed to play an important developmental role in the hippocampus by facilitating synaptic pruning.Methods:Hippocampal slices (350μm) were obtained at post-natal day (PND) 14, 21, or 28. Field EPSPs (excitatory post-synaptic potential) or whole-cell EPSCs (excitatory post-synaptic conductance) were recorded from the DG (dentate gyrus) in response to medial perforant path activation. Low-frequency stimulation (LFS; 900 pulses; 120 s pulse) was used to induce LTD.Results:Whole-cell recordings indicated that EtOH exposure at 50mM did not significantly impact ensemble NMDAr EPSCs in slices obtained from animals in the PND14 or 21 groups, but it reliably produced a modest inhibition in the PND28 group. Increasing the concentration to 100 mM resulted in a modest inhibition of NMDAr EPSCs in all three groups. LTD induction and maintenance was equivalent in magnitude in all three age groups in control conditions, however, and surprisingly, NMDA antagonist AP5 only reliably blocked LTD in the PND21 and 28 age groups. The application of 50 mM EtOH attenuated LTD in all three age groups, however increasing the concentration to 100 mM did not reliably inhibit LTD.Conclusions:These results indicate that the effect of EtOH on NMDAr-EPSCs recorded from DGCs is both age and concentration dependent in juveniles. Low concentrations of EtOH can attenuate, but did not block LTD in the DG. The effects of EtOH on LTD do not align well with it’s effects on NNMDA receptors.

Optimization of membrane excitability for predictive homeostasis of spike generation

We have proposed that membrane excitability implements “predictive homeostasis” by predicting the amplitude of excitatory postsynaptic conductances (EPSGs) and generating a spike when EPSG amplitude exceeds the expectation. A spike would therefore represent a “positive prediction error.” “Excitability” measures distance from spike threshold and corresponds to the expectation. If the expectation is optimal, the peak of the excitatory postsynaptic potential (EPSP) will be precisely at spike threshold, and therefore the spike probability would be 0.5 and the spike output would be maximally sensitive to EPSG amplitude. Simultaneous recordings of retinogeniculate input and thalamocortical spike output support the theory by showing that spike probability is near 0.5 on average. This appears random to an external observer, but is maximally informative to the neuron. If the theory is correct, we should be able to predict the membrane properties of neurons given knowledge of the natural patterns of synaptic excitation that they receive. There are numerous temporal patterns of synaptic excitation in any neuron, and we believe that there are numerous homeostatic synapses and ion channels that contribute to predictive homeostasis. We would like to relate a specific pattern to a specific property of a homeostatic ion channel. We illustrate our approach by finding the optimal homeostatic leak conductance for a neuron that receives two EPSGs separated by 5 ms (Fig. ​(Fig.1).1). We propose that the optimal conductance is the one that minimizes the sum of the squared “residuals,” where the residual is the difference between the peak of the real EPSG and that of the “threshold EPSG” that would be required to cause an EPSP that reaches precisely to spike threshold (Fig. ​(Fig.1).1). Given that the tested intervals of 5 and 10 ms are short enough to allow temporal summation of the EPSPs (Fig. ​(Fig.1B),1B), the optimal leak conductance will necessary be too high and too low at the time of the first and second EPSGs, respectively (Fig. ​(Fig.1C).1C). Homeostasis could be better maintained by dynamic inhibitory conductances that increase following the onset of the first EPSG and thereby suppress the EPSP following the second EPSG. We propose that A-type K+ and GABAA Cl- channels serve this function in real neurons. We plan to test this hypothesis by using the method described here to estimate the optimal densities or kinetics of these channels and comparing them with experimentally measured estimates. Figure 1 Finding the optimal homeostatic conductance. A neuron with only a leak conductance (reversal at -70 mV) and spike mechanism was simulated using NEURON software. A. The method of measuring distance from optimality. Top, the neuron received two EPSGs of ...

The meaning of spikes from the neuron's point of view: predictive homeostasis generates the appearance of randomness.

The conventional interpretation of spikes is from the perspective of an external observer with knowledge of a neuron’s inputs and outputs who is ignorant of the contents of the “black box” that is the neuron. Here we consider a neuron to be an observer and we interpret spikes from the neuron’s perspective. We propose both a descriptive hypothesis based on physics and logic, and a prescriptive hypothesis based on biological optimality. Our descriptive hypothesis is that a neuron’s membrane excitability is “known” and the amplitude of a future excitatory postsynaptic conductance (EPSG) is “unknown”. Therefore excitability is an expectation of EPSG amplitude and a spike is generated only when EPSG amplitude exceeds its expectation (“prediction error”). Our prescriptive hypothesis is that a diversity of synaptic inputs and voltage-regulated ion channels implement “predictive homeostasis”, working to insure that the expectation is accurate. The homeostatic ideal and optimal expectation would be achieved when an EPSP reaches precisely to spike threshold, so that spike output is exquisitely sensitive to small variations in EPSG input. To an external observer who knows neither EPSG amplitude nor membrane excitability, spikes would appear random if the neuron is making accurate predictions. We review experimental evidence that spike probabilities are indeed maintained near an average of 0.5 under natural conditions, and we suggest that the same principles may also explain why synaptic vesicle release appears to be “stochastic”. Whereas the present hypothesis accords with principles of efficient coding dating back to Barlow (1961), it contradicts decades of assertions that neural activity is substantially “random” or “noisy”. The apparent randomness is by design, and like many other examples of apparent randomness, it corresponds to the ignorance of external macroscopic observers about the detailed inner workings of a microscopic system.

Interpyramid Spike Transmission Stabilizes the Sparseness of Recurrent Network Activity

Cortical synaptic strengths vary substantially from synapse to synapse and exhibit a skewed distribution with a small fraction of synapses generating extremely large depolarizations. Using multiple whole-cell recordings from rat hippocampal CA3 pyramidal cells, we found that the amplitude of unitary excitatory postsynaptic conductances approximates a lognormal distribution and that in the presence of synaptic background noise, the strongest fraction of synapses could trigger action potentials in postsynaptic neurons even with single presynaptic action potentials, a phenomenon termed interpyramid spike transmission (IpST). The IpST probability reached 80%, depending on the network state. To examine how IpST impacts network dynamics, we simulated a recurrent neural network embedded with a few potent synapses. This network, unlike many classical neural networks, exhibited distinctive behaviors resembling cortical network activity in vivo. These behaviors included the following: 1) infrequent ongoing activity, 2) firing rates of individual neurons approximating a lognormal distribution, 3) asynchronous spikes among neurons, 4) net balance between excitation and inhibition, 5) network activity patterns that was robust against external perturbation, 6) responsiveness even to a single spike of a single excitatory neuron, and 7) precise firing sequences. Thus, IpST captures a surprising number of recent experimental findings in vivo. We propose that an unequally biased distribution with a few select strong synapses helps stabilize sparse neuronal activity, thereby reducing the total spiking cost, enhancing the circuit responsiveness, and ensuring reliable information transfer.

Barrages of Synaptic Activity Control the Gain and Sensitivity of Cortical Neurons

Ongoing synaptic activity, ever present in cortical neurons, may vary widely in its amplitude and characteristics, potentially having a strong influence on neuronal processing. Intracellular recordings in layer 5 pyramidal cells in prefrontal and visual cortical slices maintained in vitro revealed spontaneous periods of synaptic bombardment. Testing the responsiveness of these cortical cells to synaptic inputs or the injection of artificial excitatory postsynaptic conductances of various amplitudes revealed that background synaptic activity dramatically increased the probability of response to small inputs, decreased the slope of the input-output curve, and decreased both the latency and jitter of action potential activation. Examining the effects of different components of synaptic barrages (namely, depolarization, increase in membrane conductance, and increase in membrane potential variance) revealed that the effects observed were dominated by the membrane depolarization and increase in variance. Depolarization increased the peak cross-correlation between injected complex in vivo-like waveforms through enhancement of responsiveness to small inputs, whereas increases in variance did so through a shift in firing mode from one of threshold detection to probabilistic discharge. These results indicate that rapid increases in neuronal responsiveness, as well as increases in spike timing precision, can be achieved through balanced barrages of excitatory and inhibitory synaptic activity.

Activation of the TRPC1 cation channel by metabotropic glutamate receptor mGluR1.

Group I metabotropic glutamate receptors (consisting of mGluR1 and mGluR5) are G-protein-coupled neurotransmitter receptors that are found in the perisynaptic region of the postsynaptic membrane. These receptors are not activated by single synaptic volleys but rather require bursts of activity. They are implicated in many forms of neural plasticity including hippocampal long-term potentiation and depression, cerebellar long-term depression, associative learning, and cocaine addiction. When activated, group I mGluRs engage two G-protein-dependent signalling mechanisms: stimulation of phospholipase C and activation of an unidentified, mixed-cation excitatory postsynaptic conductance (EPSC), displaying slow activation, in the plasma membrane. Here we report that the mGluR1-evoked slow EPSC is mediated by the TRPC1 cation channel. TRPC1 is expressed in perisynaptic regions of the cerebellar parallel fibre-Purkinje cell synapse and is physically associated with mGluR1. Manipulations that interfere with TRPC1 block the mGluR1-evoked slow EPSC in Purkinje cells; however, fast transmission mediated by AMPA-type glutamate receptors remains unaffected. Furthermore, co-expression of mGluR1 and TRPC1 in a heterologous system reconstituted a mGluR1-evoked conductance that closely resembles the slow EPSC in Purkinje cells.

Chapter 27 Thalamic organization and function after Cajal

Cajal's many contributions to understanding the thalamus have been hidden by his body of work on the cerebral cortex. He delineated many thalamic nuclei in rodents, defined afferent fibers, thalamocortical relay neurons and interneurons, was first to demonstrate thalamocortical fibers and their terminations in the cortex, and recognized the feed-back provided by corticothalamic fibers. This presentation outlines modern methods for identifying classes of thalamic neurons, their chemical characteristics, synaptology and differential connections, and describes the intrinsic circuitry of the thalamus, showing how interactions between GABAergic cells of the reticular nucleus and glutamatergic relay cells underlie rhythmic activities of neurons in the thalamo-cortico-thalamic network, activities associated with changes in the conscious state, and which are generated and maintained by the corticothalamic projection. Corticothalamic fibers interact with reticular nucleus cells and relay cells through NMDA, AMPA and metabotropic receptors while interactions between reticular nucleus cells and relay cells are mediated by GABAA and GABAB receptors. Differing strengths of synaptic input to the two cell types, from which oscillatory behavior commences, depend upon differential expression at individual synapses of specific AMPA receptor subunits which modulate excitatory postsynaptic conductances. Two classes of relay cells can be distinguished by differential staining for calbindin and parvalbumin. The first forms a matrix in the thalamus, unconstrained by nuclear borders; the second is concentrated in certain nuclei in which it forms the topographically organized core. In projecting diffusely to the cortex, calbindin cells provide a substrate for binding together activities of multiple cortical areas that receive focused input from single thalamic nuclei. This, and the presence of specific and diffuse corticothalamic projections may serve to promote coherent activity of large populations of cortical and thalamic neurons in perception, attention and conscious awareness.

Distance-Dependent Increase in AMPA Receptor Number in the Dendrites of Adult Hippocampal CA1 Pyramidal Neurons

The Schaffer collateral pathway provides hippocampal CA1 pyramidal cells with a fairly homogeneous excitatory synaptic input that is spread out across several hundred micrometers of their apical dendritic arborizations. A progressive increase in synaptic conductance, with distance from the soma, has been reported to reduce the location dependence that should result from this arrangement. The excitatory synaptic contacts within this pathway primarily use AMPA- and NMDA-type glutamate receptors. To investigate the underlying mechanism of the increased distal excitatory postsynaptic conductance, we used outside-out patches and a fast application system to characterize the properties and distribution of synaptic glutamate receptors across the range of apical dendrites receiving Schaffer collateral input. We observed an approximately twofold increase in AMPA-mediated current amplitude (0.3-0.6 nA) in the range of CA1 apical dendrites that receive a uniform density of Schaffer collateral input (approximately 100-250 micrometer from soma). NMDA-mediated current amplitude, however, remained unchanged. We analyzed the current kinetics, agonist affinity, single-channel conductance, maximum open probability, and reversal potential of AMPA receptors and did not find any differences. Instead, the number of AMPA receptors present in our patches increased approximately twofold. These data suggest that an increase in the number of AMPA receptors present at distal synapses may play an important role in the distance-dependent scaling of Schaffer collateral synapses.

Role of glial glutamate transporters in the facilitatory action of FK960 on hippocampal neurotransmission

We found previously that N-(4-acetyl-1-piperazinyl)- p-fluorobenzamide monohydrate (FK960) facilitated hippocampal neurotransmission in the dentate gyrus of rat hippocampal slices. The present study was conducted to understand the mechanism underlying the facilitatory action of FK960. The facilitation was inhibited by H-89, an inhibitor of cAMP-dependent protein kinase (PKA), but it was not affected by cycloheximide, a protein synthesis blocker. In cultured rat hippocampal neurons, the drug had no effect on either spontaneous miniature excitatory postsynaptic currents or whole-cell membrane currents evoked by glutamate, kainate, or NMDA, suggesting that the facilitatory action of FK960 is not caused by increasing presynaptic transmitter release or excitatory postsynaptic conductances. FK960 inhibited responses of the glial glutamate transporter, GLT-1, expressed in Xenopus oocytes, and a similar effect was found with cultured rat astrocytes. The FK960 action was inhibited in the presence of H-89. The results of the present study thus suggest that FK960 facilitates hippocampal neurotransmission by inhibiting GLT-1 glial glutamate reuptake via a PKA pathway, thereby increasing synaptic glutamate concentrations.

Differences in quantal amplitude reflect GluR4- subunit number at corticothalamic synapses on two populations of thalamic neurons.

Low-frequency thalamocortical oscillations that underlie drowsiness and slow-wave sleep depend on rhythmic inhibition of relay cells by neurons in the reticular nucleus (RTN) under the influence of corticothalamic fibers that branch to innervate RTN neurons and relay neurons. To generate oscillations, input to RTN predictably should be stronger so disynaptic inhibition of relay cells overcomes direct corticothalamic excitation. Amplitudes of excitatory postsynaptic conductances (EPSCs) evoked in RTN neurons by minimal stimulation of corticothalamic fibers were 2.4 times larger than in relay neurons, and quantal size of RTN EPSCs was 2.6 times greater. GluR4-receptor subunits labeled at corticothalamic synapses on RTN neurons outnumbered those on relay cells by 3.7 times, providing a basis for differences in synaptic strength.

Progression of change in NMDA, non-NMDA, and metabotropic glutamate receptor function at the developing corticothalamic synapse.

The development of receptor function at corticothalamic synapses during the first 20 days of postnatal development is described. Whole cell excitatory postsynaptic currents (EPSCs) were evoked in relay neurons of the ventral posterior nucleus (VP) by stimulation of corticothalamic fibers in in vitro slices of mouse brain from postnatal day 1 (P1). During P1-P12, excitatory postsynaptic conductances showed strong voltage dependence at peak current and at 100 ms after the stimulus and were almost completely antagonized by -2-amino-5-phosphonopentoic acid (APV), indicating that N-methyl--aspartate (NMDA) receptor-mediated currents dominate corticothalamic EPSCs at this time. After P12, in 42% of cells, excitatory postsynaptic conductances showed no voltage-dependence at peak current but still showed voltage-dependence 100-ms poststimulus. This voltage-dependent conductance was antagonized by APV. The nonvoltage-dependent component was APV resistant, showed fast decay, and was antagonized by the nonNMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In the remaining 58% of cells after P12, excitatory postsynaptic conductances showed moderate voltage dependence at peak conductance and strong voltage dependence 100 ms after the stimulus. Analysis of EPSCs before and after APV showed a significant increase in the relative contribution of the non-NMDA conductance after the second postnatal week. From P1 to P16, there was a significant decrease in the time constant of decay of the NMDA EPSC but no change in the voltage dependence of the NMDA response. After P8, slow EPSPs, 1.5-30 s in duration and mediated by metabotropic glutamate receptors (mGluRs), could be evoked by high-frequency stimulation of corticothalamic fibers in the presence of APV and CNQX. Similar slow depolarizations could be evoked by local application of the mGluR agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) but from P0. Both conductances were blocked by the mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine. Hence functional mGluR receptors are present on VP cells from birth, but their synaptic activation at corticothalamic synapses can only be detected after P8. In voltage clamp, the extrapolated reversal potential of the t-ACPD current, with potassium gluconate-based internal solution, was +12 +/- 10 (SE) mV, and the measured reversal potential with cesium gluconate-based internal solution was 1.5 +/- 9.9 mV, suggesting that the mGluR-mediated depolarization was mediated by a nonselective cation current. Replacement of NaCl in the external solution caused the reversal potential of the current to shift to -18 +/- 2 mV, indicating that Na+ is a charge carrier in the current. The current amplitude was not reduced by application of Cs+, Ba2+, and Cd2+, indicating that the t-ACPD current was distinct from the hyperpolarization-activated cation current (IH) and distinct from certain other previously characterized mGluR-activated, nonselective cation conductances.

Stochastic threshold characterization of the intensity of active channel dynamical action potential generation.

Stochastic threshold characterization of the intensity of active channel dynamical action potential generation. J. Neurophysiol. 78: 2616-2630, 1997. This paper develops a stochastic intensity description for action potential generation formulated in terms of stochastic processes, which are direct analogues of the physiological processes of the pre- and postsynaptic complex of the cochlear nerve: 1) neurotransmitter release is modeled as an inhomogeneous Poisson counting process with release intensity mu t, 2) the excitatory postsynaptic conductance (EPSC) process is modeled as a marked, linearly filtered Poisson process resulting from the linear superposition of standard shaped postsynaptic conductances of size G, and 3) action potential generation is modeled as resulting from the EPSC exceeding a random threshold determined by active channel dynamics of the Hodgkin-Huxley type. The random threshold is defined to be the least upper bound in the size of a standard-shaped neurotransmitter release injected at time t given the previous action potential time and the number of releases occurring in a short preconditioning time increment. The action potential process is modeled as a self-exciting point process with stochastic intensity resulting from the probability that the random threshold process crosses the threshold in some small time increment that is a function of time since previous action potential, release intensity, and the probability that a single synaptic event exceeds the stochastic threshold. The stochastic intensity model is consistent with a direct simulation of the nonlinear Hodgkin-Huxley differential equations over a variety of parameters for the vesicle release intensity, vesicle size, vesicle duration, and temperatures. Results are presented showing that the regularity properties seen in the vestibular primary afferent in the lizard, Calotes versicolor, associated with a slow-to-activate potassium channel resulting in a long afterhyperpolarization can be accommodated directly by the stochastic intensity description. The stimulus dependence of the model is attributed to synaptic transmission and the probabilistic nature to the threshold conductance process, which is dependent upon the EPSC process. The stochastic intensity is seen to have a form consistent with the phenomenologically based Siebert-Gaumond model, a stimulus-related function of time multiplied by a refractory-related function of time since previous action potential.

Propagating neuronal discharges in neocortical slices: computational and experimental study.

We studied the propagation of paroxysmal discharges in disinhibited neocortical slices by developing and analyzing a model of excitatory regular-spiking neocortical cells with spatially decaying synaptic efficacies and by field potential recording in rat slices. Evoked discharges may propagate both in the model and in the experiment. The model discharge propagates as a traveling pulse with constant velocity and shape. The discharge shape is determined by an interplay between the synaptic driving force and the neuron's intrinsic currents, in particular the slow potassium current. In the model, N-methyl-D-aspartate (NMDA) conductance contributes much less to the discharge velocity than amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) conductance. Blocking NMDA receptors experimentally with 2-amino-5-phosphonovaleric acid (APV) has no significant effect on the discharge velocity. In both model and experiments, propagation occurs for AMPA synaptic coupling gAMPA above a certain threshold, at which the velocity is finite (non-zero). The discharge velocity grows linearly with the gAMPA for gAMPA much above the threshold. In the experiments, blocking AMPA receptors gradually by increasing concentrations of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the perfusing solution results in a gradual reduction of the discharge velocity until propagation stops altogether, thus confirming the model prediction. When discharges are terminated in the model by the slow potassium current, a network with the same parameter set may display discharges with several forms, which have different velocities and numbers of spikes; initial conditions select the exhibited pattern. When the discharge is also terminated by strong synaptic depression, there is only one discharge form for a particular parameter set; the velocity grows continuously with increased synaptic conductances. No indication for more than one discharge velocity was observed experimentally. If the AMPA decay rate increases while the maximal excitatory postsynaptic conductance (EPSC) a cell receives is kept fixed, the velocity increases by approximately 20% until it reaches a saturated value. Therefore the discharge velocity is determined mainly by the cells' integration time of input EPSCs. We conclude, on the basis of both the experiments and the model, that the total amount of excitatory conductance a typical cell receives in a control slice exhibiting paroxysmal discharges is only approximately 5 times larger than the excitatory conductance needed for raising the potential of a resting cell above its action potential threshold.