Inhibitory synaptic plasticity regulates pyramidal neuron spiking in the rodent hippocampus

Spike-timing modifies the efficacy of both excitatory and inhibitory synapses onto CA1 pyramidal neurons in the rodent hippocampus. Repetitively spiking the presynaptic neuron before the postsynaptic neuron induces inhibitory synaptic plasticity, which results in a depolarization of the reversal potential for GABA (E(GABA)). Our goal was to determine how inhibitory synaptic plasticity regulates CA1 pyramidal neuron spiking in the rat hippocampus. We demonstrate electrophysiologically that depolarizing E(GABA) by 24.7 mV increased the spontaneous action potential firing frequency of cultured hippocampal neurons 254% from 0.12+/-0.07 Hz to 0.44+/-0.13 Hz (n=11; P<0.05). Next we used a single compartment model of a CA1 pyramidal neuron to explore in detail how inhibitory synaptic plasticity of feedforward and feedback inhibition regulates the generation of action potentials, spike latency, and the minimum excitatory conductance required to generate an action potential; plasticity was modeled as a depolarization of E(GABA), which effectively weakens inhibition. Depolarization of E(GABA) at feedforward and feedback inhibitory synapses decreased the latency to the 1st spike by 2.27 ms, which was greater that the sum of the decreases produced by depolarizing E(GABA) at feedforward (0.85 ms) or feedback inhibitory synapses (0.02 ms) alone. In response to a train of synaptic inputs, depolarizing E(GABA) decreased the inter-spike interval and increased the number of output spikes in a frequency dependent manner, improving the reliability of input-output transmission. Moreover, a depolarizing shift in E(GABA) at feedforward and feedback synapses triggered by spike trains recorded from CA1 pyramidal layer neurons during field theta from anesthetized rats, significantly increased spiking on the up- and down-strokes of the first half of the theta rhythm (P<0.05), without changing the preferred phase of firing (P=0.783). This study provides the first explanation of how depolarizing E(GABA) affects pyramidal cell output within the hippocampus.     

Interregional synaptic competition in neurons with multiple STDP-inducing signals

Neocortical layer 5 (L5) pyramidal cells have at least two spike initiation zones: Na(+) spikes are generated near the soma, and Ca(2+) spikes at the apical dendritic tuft. These spikes interact with each other and serve as signals for synaptic plasticity. The present computational study explores the implications of having two spike-timing-dependent plasticity (STDP) signals in a neuron, each with its respective regional population of synaptic "pupils." In a detailed model of an L5 pyramidal neuron, competition emerges between synapses belonging to different regions, on top of the competition among synapses within each region, which characterizes the STDP mechanism. Interregional competition results in strengthening of one group of synapses, which ultimately dominates cell firing, at the expense of weakening synapses in other regions. This novel type of competition is inherent to dendrites with multiple regional signals for Hebbian plasticity. Surprisingly, such interregional competition exists even in a simplified model of two identical coupled compartments. We find that in a model of an L5 pyramidal cell, the different synaptic subpopulations "live in peace" when the induction of Ca(2+) spikes requires the back-propagating action potential (BPAP). Thus we suggest a new key role for the BPAP, to maintain the balance between synaptic efficacies throughout the dendritic tree, thereby sustaining the functional integrity of the entire neuron.     

A role for short-term synaptic facilitation and depression in the processing of intensity information in the auditory brain stem

The nature of the synaptic connection from the auditory nerve onto the cochlear nucleus neurons has a profound impact on how sound information is transmitted. Short-term synaptic plasticity, by dynamically modulating synaptic strength, filters information contained in the firing patterns. In the sound-localization circuits of the brain stem, the synapses of the timing pathway are characterized by strong short-term depression. We investigated the short-term synaptic plasticity of the inputs to the bird's cochlear nucleus angularis (NA), which encodes intensity information, by using chick embryonic brain slices and trains of electrical stimulation. These excitatory inputs expressed a mixture of short-term facilitation and depression, unlike those in the timing nuclei that only depressed. Facilitation and depression at NA synapses were balanced such that postsynaptic response amplitude was often maintained throughout the train at high firing rates (>100 Hz). The steady-state input rate relationship of the balanced synapses linearly conveyed rate information and therefore transmits intensity information encoded as a rate code in the nerve. A quantitative model of synaptic transmission could account for the plasticity by including facilitation of release (with a time constant of approximately 40 ms), and a two-step recovery from depression (with one slow time constant of approximately 8 s, and one fast time constant of approximately 20 ms). A simulation using the model fit to NA synapses and auditory nerve spike trains from recordings in vivo confirmed that these synapses can convey intensity information contained in natural train inputs.     

Frequency-selective augmenting responses by short-term synaptic depression in cat neocortex

Thalamic stimulation at frequencies between 5 and 15 Hz elicits incremental or 'augmenting' cortical responses. Augmenting responses can also be evoked in cortical slices and isolated cortical slabs in vivo . Here we show that a realistic network model of cortical pyramidal cells and interneurones including short-term plasticity of inhibitory and excitatory synapses replicates the main features of augmenting responses as obtained in isolated slabs in vivo . Repetitive stimulation of synaptic inputs at frequencies around 10 Hz produced postsynaptic potentials that grew in size and carried an increasing number of action potentials resulting from the depression of inhibitory synaptic currents. Frequency selectivity was obtained through the relatively weak depression of inhibitory synapses at low frequencies, and strong depression of excitatory synapses together with activation of a calcium-activated potassium current at high frequencies. This network resonance is a consequence of short-term synaptic plasticity in a network of neurones without intrinsic resonances. These results suggest that short-term plasticity of cortical synapses could shape the dynamics of synchronized oscillations in the brain.     

Synaptic origin of the respiratory-modulated activity of laryngeal motoneurons

To determine the synaptic source of the respiratory-related activity of laryngeal motoneurons, spike-triggered averaging of the membrane potentials of laryngeal motoneurons was conducted using spikes of respiratory neurons located between the Bötzinger complex and the rostral ventral respiratory group as triggers in decerebrate, paralyzed cats. We identified one excitatory and two inhibitory sources for inspiratory laryngeal motoneurons, and two inhibitory sources for expiratory laryngeal motoneurons. In inspiratory laryngeal motoneurons, monosynaptic excitatory postsynaptic potentials were evoked by spikes of inspiratory neurons with augmenting firing patterns, and monosynaptic inhibitory postsynaptic potentials (IPSPs) were evoked by spikes of expiratory neurons with decrementing firing patterns and by spikes of inspiratory neurons with decrementing firing patterns. In expiratory laryngeal motoneurons, monosynaptic IPSPs were evoked by spikes of inspiratory neurons with decrementing firing patterns and by spikes of expiratory neurons with augmenting firing patterns. We conclude that various synaptic inputs from respiratory neurons contribute to shaping the respiratory-related trajectory of membrane potential of laryngeal motoneurons.     

Excitatory and inhibitory synaptic inputs shape the discharge pattern of pump neurons of the nucleus tractus solitarii in the rat

The second-order relay neurons of the slowly-adapting pulmonary stretch receptors (SARs) are called pump neurons (P cells) and are located in the nucleus tractus solitarii (NTS). We have shown recently that P cells do not act merely as simple relay neurons of SAR afferents but also receive rhythmic inputs from the central respiratory system. This study aimed to analyze two aspects of the respiratory inputs to P cells: (1) suppression of P cell firing at early inspiration (eI suppression) and (2) facilitation of P cell firing at around the period from late inspiration to early expiration (IE facilitation). This study employed extracellular recordings combined with iontophoretic applications of neuroactive drugs to single P cells, in Nembutal-anesthetized, paralyzed, and artificially ventilated rats. The results showed that several excitatory and inhibitory neurotransmitters were involved in these synaptic events. First, the glycine antagonist strychnine and the GABA_A antagonist bicuculline were applied to identify the neurotransmitters acting in eI suppression. Strychnine greatly diminished eI suppression, but bicuculline had little effect. This suggested that eI suppression was elicited by inspiratory neurons that were glycinergic and had a decrementing firing pattern. Second, on the other hand bicuculline markedly enhanced IE facilitation as well as the baseline frequency of P cell firing. The enhancement of IE facilitation was distinctive even when the effects of increased baseline firing on this enhancement were taken into account. Third, IE facilitation was diminished by applications of the NMDA glutamate receptor antagonists D-2-amino-5-phosphonovaleric acid (APV) and dizocilpine (MK-801). These results suggested that glutamatergic synapses on P cells from some unidentified respiratory neurons form excitatory inputs for IE facilitation and GABA_A receptor-mediated processes control the strength of IE facilitation, possibly at the presynaptic level. Finally, iontophoretic application of the non-NMDA glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2, 3-dione disodium (CNQX), almost completely abolished P cell firing in response to both lung inflation and electrical stimulation of the vagus nerve. This confirmed the previous report that glutamate is the primary neurotransmitter at the synapses between SAR afferents and P cells. We concluded that complicated synaptic inputs involving glycinergic and GABAergic inhibitions, and non-NMDA and NMDA glutamate receptor-mediated excitations form the basic pattern of P cell firing. Received: 31 March 1999 / Accepted: 8 June 1999     

Improvement of phase information at low sound frequency in nucleus magnocellularis of the chicken

Nucleus magnocellularis (NM) is one of the subnuclei of the avian cochlear nucleus and has a role of extracting the temporal information of sound from the auditory nerve fibers (ANFs). Neurons in NM are varied along the tonotopic axis in synaptic transmission and membrane excitability and are high-fidelity relay neurons at the high to middle characteristic frequency (CF) regions. Here we have compared the firing properties between ANFs and NM neurons in vivo and found that at high but not near threshold intensities, spike firings are more phase-locked in NM than in ANFs in the CF region <500 Hz. Moreover, NM shows reduced occurrence of multiple spikes within one cycle of sound stimuli and higher vector strength than ANF. The improved phase-locked firing nature of NM is discussed in relation to the in vitro findings of small EPSCs in the low CF neurons (Fukui and Ohmori 2004). It is concluded that NM neurons are not simple relay neurons in the low CF region but are coincidence detectors of monoaural synaptic inputs that improve the synchronization of spike firing to auditory inputs.     

Competitive Hebbian learning through spike-timing-dependent synaptic plasticity

Hebbian models of development and learning require both activity-dependent synaptic plasticity and a mechanism that induces competition between different synapses. One form of experimentally observed long-term synaptic plasticity, which we call spike-timing-dependent plasticity (STDP), depends on the relative timing of pre- and postsynaptic action potentials. In modeling studies, we find that this form of synaptic modification can automatically balance synaptic strengths to make postsynaptic firing irregular but more sensitive to presynaptic spike timing. It has been argued that neurons in vivo operate in such a balanced regime. Synapses modifiable by STDP compete for control of the timing of postsynaptic action potentials. Inputs that fire the postsynaptic neuron with short latency or that act in correlated groups are able to compete most successfully and develop strong synapses, while synapses of longer-latency or less-effective inputs are weakened.     

Modeling inhibitory plasticity in the electrosensory system of mormyrid electric fish

Mathematical analyses and computer simulations are used to study the adaptation induced by plasticity at inhibitory synapses in a cerebellum-like structure, the electrosensory lateral line lobe (ELL) of mormyrid electric fish. Single-cell model results are compared with results obtained at the system level in vivo. The model of system level adaptation uses detailed temporal learning rules of plasticity at excitatory and inhibitory synapses onto Purkinje-like neurons. Synaptic plasticity in this system depends on the time difference between pre- and postsynaptic spikes. Adaptation is measured by the ability of the system to cancel a reafferent electrosensory signal by generating a negative image of the predicted signal. The effects of plasticity are tested for the relative temporal correlation between the inhibitory input and the sensory input, the gain of the sensory signal, and the presence of shunting inhibition. The model suggests that the presence of plasticity at inhibitory synapses improves the function of the system if the inhibitory inputs are temporally correlated with a predictable electrosensory signal. The functional improvements include an increased range of adaptability and a higher rate of system level adaptation. However, the presence of shunting inhibition has little effect on the dynamics of the model. The model quantifies the rate of system level adaptation and the accuracy of the negative image. We find that adaptation proceeds at a rate comparable to results obtained from experiments in vivo if the inhibitory input is correlated with electrosensory input. The mathematical analysis and computer simulations support the hypothesis that inhibitory synapses in the molecular layer of the ELL change their efficacy in response to the timing of pre- and postsynaptic spikes. Predictions include the rate of adaptation to sensory stimuli, the range of stimulus amplitudes for which adaptation is possible, the stability of stored negative images, and the timing relations of a temporal learning rule governing the inhibitory synapses. These results may be generalized to other adaptive systems in which plasticity at inhibitory synapses obeys similar learning rules.     

Background synaptic activity modulates the response of a modeled purkinje cell to paired afferent input

We studied the possible effects of background excitatory and inhibitory synaptic activity on Purkinje cell responses to paired pulse inputs using a morphologically and physiologically detailed compartmental model. Paired-pulse inputs were provided via synapses associated with the ascending segment of the granule cell axon in the presence of variable amounts of background synaptic input provided by parallel fibers and inhibitory interneurons. The results predict the amplitude and dynamics of the somatic and dendritic responses to paired ascending segment inputs are modulated by the level of background synaptic activity, the basal somatic firing rate of the Purkinje cell model does not indicate the type or degree of modulation, and the modulatory effects are mediated through dendritic calcium and calcium-activated potassium currents. These results have important consequences for the functional organization of cerebellar cortex as well as the more general issue of the modulatory as distinct from driving effects of synapses now also being considered in other regions of the mammalian brain including the cerebral cortex.     

Synaptic competition in the lateral amygdala and the stimulus specificity of conditioned fear: a biophysical modeling study

Competitive synaptic interactions between principal neurons (PNs) with differing intrinsic excitability were recently shown to determine which dorsal lateral amygdala (LAd) neurons are recruited into a fear memory trace. Here, we explored the contribution of these competitive interactions in determining the stimulus specificity of conditioned fear associations. To this end, we used a realistic biophysical computational model of LAd that included multi-compartment conductance-based models of 800 PNs and 200 interneurons. To reproduce the continuum of spike frequency adaptation displayed by PNs, the model included three subtypes of PNs with high, intermediate, and low spike frequency adaptation. In addition, the model network integrated spatially differentiated patterns of excitatory and inhibitory connections within LA, dopaminergic and noradrenergic inputs, extrinsic thalamic and cortical tone afferents to simulate conditioned stimuli as well as shock inputs for the unconditioned stimulus. Last, glutamatergic synapses in the model could undergo activity-dependent plasticity. Our results suggest that plasticity at both excitatory (PN–PN) and di-synaptic inhibitory (PN–ITN and, particularly, ITN–PN) connections are major determinants of the synaptic competition governing the assignment of PNs to the memory trace. The model also revealed that training-induced potentiation of PN–PN synapses promotes, whereas that of ITN–PN synapses opposes, stimulus generalization. Indeed, suppressing plasticity of PN–PN synapses increased, whereas preventing plasticity of interneuronal synapses decreased the CS specificity of PN recruitment. Overall, our results indicate that the plasticity configuration imprinted in the network by synaptic competition ensures memory specificity. Given that anxiety disorders are characterized by tendency to generalize learned fear to safe stimuli or situations, understanding how plasticity of intrinsic LAd synapses regulates the specificity of learned fear is an important challenge for future experimental studies.     

Retinogeniculate synaptic properties controlling spike number and timing in relay neurons

Retinal ganglion cells (RGC) transmit visual signals to thalamocortical relay neurons in the lateral geniculate nucleus via retinogeniculate synapses. Relay neuron spike patterns do not simply reflect those of RGCs, but the mechanisms controlling this transformation are not well understood. We therefore examined synaptic properties controlling the strength and precision of relay neuron firing in mouse (p28-33) brain slices using physiological stimulation patterns and a combination of current clamp and dynamic clamp. In tonic mode (-55 mV), activation of single RGC inputs elicited stereotyped responses in a given neuron. In contrast, responses in different neurons varied from unreliable, to faithfully following, to a gain in the number of spikes. Dynamic clamp experiments indicated these different responses primarily reflected variability in the amplitudes of the N-methyl-d-aspartate (NMDA) and AMPA components. Each of these components played a distinct role in transmission. The AMPA component evoked a single precisely timed, short-latency spike per stimulus, but efficacy decreased during repetitive stimulation due to desensitization and depression. The NMDA component elicited longer-latency spikes and multiple spikes per stimulus and became more effective during repetitive stimuli that led to NMDA current summation. We found that in burst mode (-75 mV), where low-threshold calcium spikes are activated, AMPA and NMDA components and synaptic plasticity influenced spike number, but no combination enabled relay cells to faithfully follow the stimulus. Thus the characteristics of AMPA and NMDA currents, the ratio of these currents and use-dependent plasticity interact to shape how RGC activity is conveyed to relay neurons.     

Cell-specific, spike timing-dependent plasticities in the dorsal cochlear nucleus

In the dorsal cochlear nucleus, long-term synaptic plasticity can be induced at the parallel fiber inputs that synapse onto both fusiform principal neurons and cartwheel feedforward inhibitory interneurons. Here we report that in mouse fusiform cells, spikes evoked 5 ms after parallel-fiber excitatory postsynaptic potentials (EPSPs) led to long-term potentiation (LTP), whereas spikes evoked 5 ms before EPSPs led to long-term depression (LTD) of the synapse. The EPSP-spike protocol led to LTD in cartwheel cells, but no synaptic changes resulted from the reverse sequence (spike-EPSP). Plasticity in fusiform and cartwheel cells therefore followed Hebbian and anti-Hebbian learning rules, respectively. Similarly, spikes generated by summing EPSPs from different groups of parallel fibers produced LTP in fusiform cells, and LTD in cartwheel cells. LTD could also be induced in glutamatergic inputs of cartwheel cells by pairing parallel-fiber EPSPs with depolarizing glycinergic PSPs from neighboring cartwheel cells. Thus, synaptic learning rules vary with the postsynaptic cell, and may require the interaction of different transmitter systems.     

The facilitative effects of bilobalide,a unique constituent of <Emphasis Type="Italic">Ginkgo biloba</Emphasis>, on synaptic transmission and plasticity in hippocampal subfields

Bilobalide, a unique constituent of Ginkgo biloba, has been reported to potentiate population spikes in hippocampal CA1 pyramidal cells and to protect the brain against cell death. In this study, the effects of bilobalide on synaptic transmission and its plasticity in rat hippocampal subfields were electrophysiologically investigated. Bilobalide (50 μM) significantly potentiated the input–output relationship at Schaffer collateral (SC)-CA1 synapses but not at medial perforant path (MPP)-dentate gyrus (DG), lateral perforant path (LPP)-DG, or mossy fiber (MF)-CA3 synapses. Facilitative effects of bilobalide on synaptic plasticity were only observed at MPP-DG synapses, in which the induction of long-term depression was blocked in the presence of bilobalide. However, no effect on synaptic plasticity was observed at SC-CA1 synapses. These results suggest that bilobalide has differential effects on synaptic efficacy in each hippocampal subfield.     

Background firing activity in guinea-pig neocortex in vitro.

The background firing activity was recorded extracellularly in experiments on guinea-pig neocortical slices maintained in vitro. The following types of background firing activity were revealed: (i) high regular single spikes (48%), (ii) irregular single spikes (15%), (iii) bursts (7%), (iv) groups (7%), (v) mixed activity where single spikes alternated with bursts or groups (28%). The specific interspike interval distribution and the specific shape of autocorrelogram corresponded to each of these background firing activity types. Furie analysis of autocorrelograms showed periodic components in spike sequences with the maxima at 3, 12, and 28 Hz. When blocking synaptic transmission with 100 mM adenosine, about 70% of the background active cells "fell silent" and the remaining 30% of neurons continued to generate action potentials. The latter seem to be actual spontaneously active neurons, i.e. they were capable of autonomous spike generation. We failed to find any correlation between the type of neuronal firing and the ability of neurons to be spontaneously active. The selective blockade of inhibitory synapses with 100 mM picrotoxine did not practically change the character of background firing activity though the responses to stimulation became epileptic. An important conclusion to emerge from this study is that the background firing activity in cortical slices can include the actual spontaneous discharges related to intrinsic cell properties as well as those concerned with synaptic actions. Furthermore, a small number of spontaneously active neurons seem to be able to synaptically activate twice the number of cells. The inhibitory interneurons did not significantly influence the propagation of excitation with the absence of stimulation.     

Spike-timing-dependent plasticity of inhibitory synapses in the entorhinal cortex

Actions of inhibitory interneurons organize and modulate many neuronal processes, yet the mechanisms and consequences of plasticity of inhibitory synapses remain poorly understood. We report on spike-timing-dependent plasticity of inhibitory synapses in the entorhinal cortex. After pairing presynaptic stimulations at time t(pre) with evoked postsynaptic spikes at time t(post) under pharmacological blockade of excitation we found, via whole cell recordings, an asymmetrical timing rule for plasticity of the remaining inhibitory responses. Strength of response varied as a function of the time interval Deltat = t(post) - t(pre): for Deltat > 0 inhibitory responses potentiated, peaking at a delay of 10 ms. For Deltat < 0, the synaptic coupling depressed, again with a maximal effect near 10 ms of delay. We also show that changes in synaptic strength depend on changes in intracellular calcium concentrations and demonstrate that the calcium enters the postsynaptic cell through voltage-gated channels. Using network models, we demonstrate how this novel form of plasticity can sculpt network behavior efficiently and with remarkable flexibility.     

Synaptic inputs to trigeminal primary afferent neurons cause firing and modulate intrinsic oscillatory activity

In this paper, we investigated the influence of synapses on the cell bodies of trigeminal muscle spindle afferents that lie in the trigeminal mesencephalic nucleus (NVmes), using intracellular recordings in brain stem slices of young rats. Three types of synaptic responses could be evoked by electrical stimulation of the adjacent supratrigeminal, motor, and main sensory nuclei and the intertrigeminal area: monophasic depolarizing postsynaptic potentials (PSPs), biphasic PSPs, and all or none action potentials without underlying excitatory PSPs (EPSPs). Many PSPs and spikes were abolished by bath-application of 6,7-dinitroquinoxaline (DNQX) alone or combined with D,L-2-amino-5-phosphonovaleric acid (APV), suggesting that they are mediated by non-N-methyl-D-aspartate (NMDA) and NMDA glutamatergic receptors, while some action potentials were sensitive to bicuculline, indicating involvement of GABAA receptors. A number of cells showed spontaneous membrane potential oscillations, and stimulation of synaptic inputs increased the amplitude of the oscillations for several cycles, which often triggered repetitive firing. Furthermore, the oscillatory rhythm was reset by the stimulation. Our results show that synaptic inputs to muscle primary afferent neurons in NVmes from neighboring areas are mainly excitatory and that they cause firing. In addition, the inputs synchronize intrinsic oscillations, which may lead to sustained, synchronous firing in a subpopulation of afferents. This may be of importance during rapid biting and during the mastication of very hard or tough foods.     

Frequency-dependent synaptic depression and the balance of excitation and inhibition in the neocortex

The stability of cortical neuron activity in vivo suggests that the firing rates of both excitatory and inhibitory neurons are dynamically adjusted. Using dual recordings from excitatory pyramidal neurons and inhibitory fast-spiking neurons in neocortical slices, we report that sustained activation by trains of several hundred presynaptic spikes resulted in much stronger depression of synaptic currents at excitatory synapses than at inhibitory ones. The steady-state synaptic depression was frequency dependent and reflected presynaptic function. These results suggest that inhibitory terminals of fast-spiking cells are better equipped to support prolonged transmitter release at a high frequency compared with excitatory ones. This difference in frequency-dependent depression could produce a relative increase in the impact of inhibition during periods of high global activity and promote the stability of cortical circuits.     

Activity- and BDNF-induced plasticity of miniature synaptic currents in ES cell-derived neurons integrated in a neocortical network

In vitro differentiated embryonic stem (ES) cells have been proposed as potential donor cells for cell replacement therapies of neurodegenerative diseases. The functional synaptic integration of such cells appears conceivable because ES cell-derived neurons are well known to establish excitatory and inhibitory synapses. However, long-term synaptic plasticity, a prerequisite of memory formation, has not yet been demonstrated at these synapses. After in vitro differentiation and purification by immunoisolation, we co-cultured ES cell-derived neurons with neocortical explants, which strongly innervated the ES cell-derived target neurons. ES cell-derived neurons exhibited action potential firing similar to primary cultured neocortical neurons. The formation of glutamatergic synapses was indicated by AMPA receptor-mediated miniature excitatory postsynaptic currents (AMPA mEPSCs). In addition, a N-methyl-D-aspartate receptor-mediated, D-2-amino-5-phosphonopentanoic acid-sensitive mEPSC component was observed. We first studied activity-dependent homeostatic plasticity (synaptic scaling) of mEPSCs at glutamatergic synapses. Chronic blockade of action potential activity by TTX resulted in an increase in the amplitudes of AMPA mEPSCs. This indicates that ES cell-derived neurons are capable of a homeostatic regulation of postsynaptic AMPA receptors. In addition, we investigated neurotrophin-induced synaptic plasticity of mEPSCs at glutamatergic synapses. Chronic addition of brain-derived neurotrophic factor (BDNF; 100 ng/ml) to the culture medium resulted in an increase in both the frequency and the amplitudes of AMPA mEPSCs. These results suggest that BDNF induces the formation and/or the functional maturation of presynaptic release sites in parallel with an upregulation of postsynaptic AMPA receptors. Thus BDNF represents a potential co-factor that could improve functional synaptic integration of ES cell-derived neurons into neocortical networks.     

Functional properties of electrical synapses between inhibitory interneurons of neocortical layer 4

The existence of electrical synapses between GABAergic inhibitory interneurons in neocortex is well established, but their functional properties have not been described in detail. We made whole cell recordings from pairs of electrically coupled fast-spiking (FS) or low threshold-spiking (LTS) neurons, and filled some cells with biocytin for morphological reconstruction. Data were used to create compartmental cable models and to guide mathematical analysis. We analyzed the time course and amplitude of electrical postsynaptic potentials (ePSPs), the subthreshold events generated by presynaptic action potentials, in both FS and LTS neurons. The results imply that the generation of ePSPs is predominantly a linear process in both cell types for presynaptic firing of both single and repetitive spikes. Nonlinearities shape ePSPs near spike threshold, but our data suggest that the underlying synaptic current is still a linear process. Cell-to-cell electrical signaling on longer timescales also appears to be linear. Cable models of electrically coupled FS and LTS neurons imply that the analyzed electrical synapses are, on average, within 50 mum of the soma. Finally, we show that electrical coupling between 2 inhibitory cells promotes synchrony at all spiking frequencies. This contrasts with the effect of reciprocal inhibitory postsynaptic potentials (IPSPs) evoked by the same cells, which promote antisynchronous firing at frequencies less than about 100 Hz. Electrical coupling counteracts the antisynchronous behavior induced by IPSPs and facilitates spiking synchrony. Our results suggest that electrical synapses among inhibitory interneurons are most readily described as low-pass linear filters that promote firing synchrony.