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Synaptic gating is normally thought to be a mechanism for excluding synaptic input, but three recent studies show how the resting membrane potential interacts with integrative properties to act as a permissive synaptic gate.
Long-term potentiation is an enduring increase in synaptic efficacy following repeated stimulation of afferent fibers that is thought to underlie memory. In area CA1 of the hippocampus at least two forms of synaptic potentiation coexist at the same synapses; nmdaLTP and vdccLTP. NmdaLTP is induced by Ca2+ entry through NMDARs and is dependent on serine/threonine kinase activation, while vdccLTP is induced through Ca2+ entry through VDCCs and is dependent on tyrosine kinase activation. Depotentiation is a mechanism known to reverse nmdaLTP through phosphatase activation. The depotentiation of vdccLTP has not been previously investigated. We used hippocampal slices (area CA1) from male Long-Evans rats to induce vdccLTP with a 200-Hz tetanus in the presence of 50 microM APV. The 200-Hz tetanus resulted in a slowly developing vdccLTP that remained stable for at least 30 min. Thirty minutes after vdccLTP was induced, a low-frequency tetanus (3, 10, 20, 30, or 40 Hz) was applied in the presence of APV in an attempt to depotentiate vdccLTP. The 3- and 10-Hz low-frequency tetani resulted in no depotentiation. The 20- and 30-Hz tetani partially depotentiated vdccLTP (by approximately 13%), whereas the 40-Hz tetanus resulted in further potentiation. When APV was washed out prior to the 3-Hz low-frequency tetanus, the vdccLTP was completely depotentiated--presumably by NMDAR mechanisms. Our results indicate that vdccLTP is resistant to depotentiation under low-frequency stimulation conditions that readily depotentiate nmdaLTP. As tetanus frequencies are increased a small depotentiation is observed, suggesting that vdccLTP can be depotentiated to a small extent. When NMDARs are unblocked, vdccLTP can be completely depotentiated by a 3-Hz low-frequency tetanus, suggesting that vdccLTP can be depotentiated via activation of NMDAR mechanisms.
Bidirectional modifications in synaptic efficacy are central components in recent models of cortical learning and memory, and we previously demonstrated both long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD) in the neocortex of the unanaesthetized adult rat. Here, we have examined the effects of N-methyl-D-aspartate receptor (NMDAR) blockade on the induction of LTD, LTP, and depotentiation of field potentials evoked in sensorimotor cortex by stimulation of the white matter in the adult, freely moving rat. High frequency (300 Hz) stimulation (HFS) was used to induce LTP and prolonged, low-frequency (1 Hz) stimulation was used to induce either depotentiation or LTD. LTD was expressed as a reduction in the amplitude of the short and long-latency field potential components, while depotentiation was expressed as a decrease in the amplitude of a previously enhanced late component. Under NMDAR blockade, HFS failed to induce LTP and instead produced a depression effect similar to LTD. Following washout of the drug, HFS induced a normal LTP effect. Unlike LTP, LTD and depotentiation were found to be NMDAR-independent in the neocortex of the freely moving rat.
In many regions of the brain, including the mammalian cortex, the magnitude and direction of activity-dependent changes in synaptic strength depend on the frequency of presynaptic stimulation (synaptic plasticity), as well as the history of activity at those synapses (metaplasticity). We present a model of a molecular mechanism of bidirectional synaptic plasticity based on the observation that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD) correlate with the phosphorylation/dephosphorylation of sites on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit protein GluR1. The primary assumption of the model, for which there is wide experimental support, is that postsynaptic calcium concentration and consequent activation of calcium-dependent protein kinases and phosphatases are the triggers for the induction of LTP/LTD. As calcium influx through the n-methyl-d-aspartate (NMDA) receptor plays a fundamental role in the induction of LTP/LTD, changes in the properties of NMDA receptor-mediated calcium influx will dramatically affect activity-dependent synaptic plasticity (metaplasticity). We demonstrate that experimentally observed metaplasticity can be accounted for by activity-dependent regulation of NMDA receptor subunit composition and function. Our model produces a frequency-dependent LTP/LTD curve with a sliding synaptic modification threshold similar to what has been proposed theoretically by Bienenstock, Cooper, and Munro and observed experimentally.
The effect of intracellular current injection on synaptic potentials and spike initiation were studied in hippocampal CA1 pyramidal cells in the in vitro slice preparation. Measures of cell charging time constant, resistance, and rheobase level were similar to those reported by other investigators working with intact preparations. Studies of spike initiation induced by injection of depolarizing ramp currents gave little evidence for a threshold accommodation in Ca1 cells. Small amplitude fast-rising spike potentials occurred spontaneously and in association with synaptic excitation of neurons. It is argued that these potentials reflect active spike generation in the dendrites.
We describe four different mechanisms that lead to oscillations in a network of two reciprocally inhibitory cells. In two cases (intrinsic release and intrinsic escape) the frequency of the network oscillation is insensitive to the threshold voltage of the synaptic potentials. In the other two cases (synaptic release and synaptic escape) the network frequency is strongly determined by the threshold voltage of the synaptic connections. The distinction between the different mechanisms blurs as the function describing synaptic activation becomes less steep and as the model neurons are removed from the relaxation regime. These mechanisms provide insight into the parameters that control network frequency in motor systems that depend on reciprocal inhibition.
Theoretical analysis of motoneuron models predicts that the cross-correlogram between motoneuron discharges and stimuli should reflect the derivative of the post-synaptic potential (PSP) in the absence of synaptic noise. The cross-correlogram peaks become wider if the amplitude of the noise is significant. To deal with this case, the linear combination of the PSP and its first derivative has been proposed as an approximation. The synaptic noise was regarded as a Gaussian stochastic process (its diffusion approximation), and the estimation of the cross-correlation function for this case is presented. The results were found to be in agreement with reported experimental data. A comparison was made with the linear combination approximation and with the reported computer simulation.
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and plays an important role in neuronal survival and plasticity in the CNS. The proform of BDNF (pro-BDNF) is secreted and cleaved extracellularly by the serine protease plasmin to mature BDNF, which potentiates synaptic plasticity and long-term potentiation. Recent findings in animal models suggest an involvement of BDNF and its genetic functional single nucleotide polymorphism in the pathogenesis of different psychiatric diseases including depression, mania, schizophrenia, eating disorders, dementia, and Huntington's disease. In the brain and serum, BDNF is modulated by different factors. It is downregulated by stress and upregulated by learning processes, several antidepressive treatments, physical activity, and dietary restriction. Measurement of BDNF serum concentrations may be of diagnostic value. Additionally, the influence of different strategies for BDNF allocation seems to be relevant for the treatment and prevention of the above psychiatric disorders.
High frequency (HF)-induced and norepinephrine (NE)-induced long-term potentiation have been hypothesized to utilize common mechanisms of induction and expression in the dentate gyrus. In vitro data tend to support this hypothesis, but few studies have been done in vivo. The present study records perforant path-evoked potentials simultaneously on two micropipettes, one filled with saline and the other with the beta-antagonist, timolol. Stimulation of the paragigantocellularis nucleus (PGi) was used as a method of producing NE release in the dentate gyrus, and thus, to assess the efficacy of beta-receptor blockade on the timolol pipette. Beta-blockade by timolol attenuated PGi-induced spike potentiation. HF-induced potentiation of the excitatory post-synaptic potential (EPSP) slope was also blocked by timolol, but HF-induced spike amplitude potentiation was unaffected. These results are consistent with an earlier report examining HF-long-term potentiation (LTP) following 6-OHDA-induced NE depletion, which showed that the EPSP slope LTP depended, for its full expression, on NE, but potentiation of the population spike amplitude component of HF-induced LTP did not. In the present study, PGi-induced potentiation of spike amplitude on the saline pipette was normal after HF-induced saturation of spike amplitude potentiation, suggesting that the mechanisms for expression of spike potentiation, as well as induction of spike potentiation, are separate for HF and NE stimulation.
Intracellular injections of Lucifer Yellow were utilized to evaluate the incidence of dye-coupling among dorsolateral septal nucleus (DLSN) neurons recorded from slice preparations of adult rat septal nuclei. Twenty percent of single injections of Lucifer Yellow resulted in pairs of labeled neurons. These dye-coupled cells were morphologically heterogeneous and did not exhibit any morphological characteristics that could be used to distinguish them from non dye-coupled neurons. The spatial separation of cell bodies and close apposition of dendrites within each pair indicated that the dye transfer site(s) were situated at dendrodendritic and/or dendrosomatic rather than somatosomatic junctions. The main axon of some dye-coupled neurons gave rise to intrinsic axon collaterals prior to exiting the nucleus indicating that these coupled neurons function as projection neurons as well as local circuit interneurons. Electrophysiological recordings of the passive membrane properties and spontaneous activity of individual dye-coupled neurons revealed no significant difference from non dye-coupled cells in the DLSN. Some neurons exhibited spontaneously occurring fast potentials which presumably represent electrotonic potentials. These fast potentials were often tightly coupled with action potentials but could be distinguished from synaptic potentials by their shape and their lack of voltage-dependent changes in amplitude. These morphological and supportive electrophysiological data provide the first indirect evidence for electrotonic coupling of dorsolateral septal neurons. The functional significance of this coupling may lie in the potential for synchronization of the output of the DLSN which could play an important role in the septal maintenance and modulation of hippocampal Theta rhythm.
Hyperpolarization of the ventrolateral thalamic cell membrane reveals a slow inward current which is not normally observed at the resting membrane potential. The response evoked by depolarizing synaptic potentials or depolarizing current pulses from a hyperpolarized potential consists of a burst of action potentials superimposed upon a slow voltage response, in contrast to the single active response evoked without the background polarization. We propose that such behavior is caused by a slow inward current that is activated at subthreshold potentials and inactivated or masked at resting potential.
The mechanisms underlying the depressant effect of adenosine on excitatory synaptic transmission were studied in rat hippocampus in vitro. The relative contribution of direct effects of adenosine upon CA1 pyramidal neurons (hyperpolarization, increased conductance) was evaluated by comparing the effects of superfused adenosine on EPSP amplitude, and on depolarizing responses to local application of glutamate. Adenosine depressed synaptic EPSPs to a greater extent than glutamate responses in 30 out of 32 cases, and its effects were independent of the site of glutamate application (somatic vs dendritic). Thus, the postsynaptic effects of adenosine, including a possible dendritic conductance that would be undetectable with somatic recordings, can only partially account for the depression of synaptic potentials observed with adenosine.
The development of neural connections between transplanted lateral geniculate nucleus (LGN) and host visual cortex (VC) was studied in slice preparations obtained from rat brain in which a fetal (embryonic day 15-17) rat LGN was transplanted to the white matter underlying the VC of a neonate rat (postnatal day 0-1). Placing a fluorescent dye (DiI) in the transplant of the fixed slices revealed that retrogradely labeled cortical cells projecting to the transplant were broadly distributed through layers II to VI at 1 week after transplantation. Three weeks after transplantation, these cells were virtually confined to layer VI. Likewise, anterograde labeling showed that cells in the transplant sent axons up to layer I with a few branches at 1 week after transplantation, while the axons were found to terminate at layer IV with many arborizations at 3 weeks after transplantation. These observations were supported by electrophysiological studies. Analysis of the antidromic responses of the cortical cells to stimulation of the transplant showed that the efferent cells projecting to the transplant were broadly distributed in layers II-VI at 1 week after transplantation, while they were virtually restricted to layer VI at 3 weeks after transplantation. Current source-density analysis of the field potentials and intracellular analysis of the synaptic potentials in the cortical cells demonstrated that geniculocortical connections were broadly established in layers II-VI at 1 week after transplantation, and were localized to layer IV and VI at 3 weeks after transplantation. These results suggest that the development of neural connections between transplanted LGN and host VC is characterized by an initial broad distribution of afferent and efferent connections without laminar specificity, and by later selection of appropriate connections to yield lamina-specific connections comparable to those in normal adult VC.
Interferons (IFN) appear to have various neuromodulatory actions. Here, we characterized the actions of IFN-alpha on the electrophysiological properties of CA1 hippocampal neurons using intracellular recordings. Superfusion of this cytokine did not alter the resting membrane potential, cell input resistance, action potentials, nor GABA-mediated fast synaptic potentials. IFN-alpha inhibited glutamate-mediated excitatory postsynaptic potentials (gEPSPs) and reversed or prevented long-term potentiation (LTP) induced by high-frequency tetanic stimulation. IFN-alpha reduced gEPSP amplitude far below its control value. Only a short-term potentiation (STP) was observed when either IFN-alpha or D-2-amino-5-phosphonovalerato (APV; NMDA receptor antagonist) were present during tetanic stimulation. After this STP in presence of APV, IFN-alpha had no effect on gEPSPs. APV had no effect on LTP when applied after tetanic stimulation and did also not prevent IFN-alpha effect on LTP. Genistein (a tyrosine kinase inhibitor) or heat inactivation prevented IFN-alpha effects. IFN-alpha also decreased the depolarization induced by local application of glutamate but did not modify those induced by NMDA. Similarly, IFN-alpha reversed the potentiation (induced by tetanic stimulation) of glutamate-induced depolarizations. IFN-alpha did not affect long-term depression (LTD) induced by low-frequency tetanic stimulation. In conclusion, IFN-alpha-induced inhibition of LTP is, at least in part, mediated by a postsynaptic effect, by tyrosine kinase activity, and by non-NMDA glutamate receptors. Inhibition of LTP by IFN-alpha unmasks LTD which is induced by the same high-frequency tetanic stimulation.
1. An electrophysiological analysis has been made of the storage of acetylcholine (ACh) in the preganglionic nerve terminals of the isolated superior cervical ganglion of the guinea-pig. The mean amplitude of excitatory post-synaptic potentials recorded intracellularly was taken as a measure of the ACh output per impulse from the terminals of a preganglionic axon.2. Prolonged repetitive stimulation of the cervical sympathetic trunk at 10 and 20 Hz in the presence of hemicholinium No. 3 led to an exponential decline of ACh output as the transmitter formed before the beginning of stimulation was depleted.3. The rate of decline of ACh output during stimulation at 20 Hz (tau = 0.83-1.95 min) was about twice as fast as that at 10 Hz (tau = 1.00-6.83 min).4. The results suggest that, during prolonged stimulation, ACh is released from a single store in the preganglionic nerve terminal and that each impulse releases a constant fraction of the store of the transmitter.
The activity of external intercostal motoneurones in the cat was studied under anaesthesia and paralysis before and after partial central deafferentation caused by single or double ipsilateral hemisections of the thoracic spinal cord. The normal efferent inspiratory discharges recorded from external intercostal nerve filaments caudal to the upper lesion were greatly reduced acutely, but activity of approximately normal intensity and phase at eupneoic levels of CO2 was restored within a few days and remained at similar levels for up to two years. The patterns of the restored activity were abnormal, with more discharges of alpha-motoneutrones during expiration than normal and a stronger modulation of the discharges by the respiratory pump than normal. A common abnormal component of the restored activity was a tonic discharge in hypocapnic apnoea, often modulated by the respiratory pump. This activity was never seen in normal animals or in those with acute lesions under similar conditions of anaesthesia. Synchronization of the discharges of alpha-motoneurones caudal to the upper lesion was studied by constructing cross-correlation histograms between paired groups of motoneurones, each group being represented by the discharges in one filament. Synchronization was stronger than normal, usually extending over a time course of +/- 20 to +/- 50 ms (broad-peak synchronization). This synchronization was particularly strong for the discharges in hypocapnic apnoea. We conclude that the restored activity was derived in large part from abnormal tonic (non-respiratory-phased) inputs, partly proprioceptive in origin, probably involving spinal cord interneurones with abnormally synchronized discharges. This conclusion is supported by intracellular measurements including respiratory drive potentials, synaptic noise and average common excitation potentials.
The whole-nerve cochlear action potential (CAP), to tone burst stimulation, was recorded before and after application of tetrodotoxin (TTX) to the intact round window (RW) membrane. TTX abolished the CAP leaving a residual negative potential without altering the summating potential (SP) or the cochlear microphonic (CM). The residual potential retained its polarity when recorded from scala vestibuli. The peak latency, amplitude, and tuning properties of the residual potential showed features similar to the CAP. Application of kainic acid to the RW membrane eliminated the residual potential, leaving the SP and CM unaltered. It is hypothesized that the sources of the residual potential are the excitatory post-synaptic potentials from the peripheral processes of afferent dendrites under the inner hair cells.
The physiology of excitable membranes is a fundamental topic in neuroscience and physiology courses at graduate and undergraduate levels. From the building blocks of ionic gradients and membrane channels whose permeability is selective and variable, we build the concepts of resting potential, action potential, and propagation in neurons and muscle fibers. Many students have an intuitive understanding of the movements of ions and the associated changes in membrane potential. For example, potassium ions leaving a cell through potassium-selective channels become unbalanced positive charges on the outside of the cell (and leave unbalanced negative charges on the inside), thus producing a potential across the membrane with the inside negative with respect to the outside. Later, when we discuss the local circuit currents that underlie propagation or the basis for extracellular stimulation, we make the general statement that "outward currents depolarize cells." Students respond with utter disbelief. Two simple additions to a discussion of membranes are suggested that permit the formulation of a consistent set of rules that apply to everything from the resting and action potentials of nerve and muscle through synaptic potentials and stimulation techniques.