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PubMed1966

Intracellular recording from spinal motoneurones in cats with post-asphyxial rigidity.

1. Intracellular recordings were obtained from lumbar spinal motoneurones in cats with post-asphyxial rigidity of the hind limbs.2. Membrane potentials, latencies and (or) appearance of excitatory post-synaptic potentials, initial segment responses and soma-dendritic spikes were not materially different from those observed in cells of normal cords.3. Dorsal root stimulation activated all the motoneurones examined through monosynaptic pathways in contrast to cells in normal cords in which such a stimulus sometimes elicits only a post-synaptic potential. In a number of cells subsequent polysynaptic activation caused a spike about 10 msec after the monosynaptic response, notwithstanding the serious interneuronal destruction which characterized these preparations.4. In a few preparations the effects of acute asphyxiation could be examined. The soma depolarized at a rate of 3-4 mV/min. Synaptic activation was more resistant to O(2) lack than antidromic and direct excitation, in contrast to the experience with normal cells. Survival times of 8.5, 11 and 16 min were found. At certain levels of depolarization ;spontaneous' spikes were observed, which, since they were preceded by post-synaptic potentials, could be considered as the result of synaptic activation.5. To account for the enhanced reflex activity of rigid preparations, it was postulated that the substantial loss of interneurones in the cord had caused denervation supersensitivity of the motoneurones to the transmitter compound without materially changing their electrical excitability.6. It was postulated that the early presynaptic failure during asphyxiation in normal preparations was dependent on a mechanism resembling presynaptic inhibition. The prolonged asphyxial survival of reflex activity in rigid preparations may be due to the destruction of interneurones involved in this form of inhibition.

Animals↗
PubMed1987

Facilitation of kindling by prior induction of long-term potentiation in the perforant path.

Previous studies have revealed that a form of synaptic potentiation resembling long-term potentiation (LTP) occurs at various sites as a result of stimulation that leads to kindling. The present study evaluates what role this synaptic potentiation plays in the development of kindling following periodic stimulation of the entorhinal cortex of the rat. LTP was repetitively induced in the pathway from the entorhinal cortex (EC) to the dentate gyrus (DG) by daily stimulation with high frequency trains that led to LTP, but did not evoke afterdischarge (AD). Subsequently, animals received stimulation designed to induce kindling (that led to AD), and this stimulation was delivered once per day until kindled seizures were induced. While repetitive induction of LTP was not sufficient to produce kindling, prior induction of LTP significantly increased the rate of subsequent kindling as evidenced by a decrease in the number of kindling stimulations required to induce the kindled state. As a group, animals that had received stimulation designed to induce LTP developed kindled seizures after an average of 10 AD's, whereas a control group that had received non-potentiating stimulation required 25 AD's. These results indicate that LTP at EC-DG synapses cannot represent the mechanism of kindling following EC stimulation. However, synaptic potentiation at this site can facilitate the development of epileptogenesis in response to subsequent activation of the perforant path.

Action Potentials↗
PubMed1976

Functional and non-functional contacts between ciliary neurones and muscle grown in vitro.

1. In cultures of chick embryo skeletal muscle and ciliary ganglia, muscle fibres near a ganglion were contacted by many individual nerve processes. Experiments were performed to determine if these muscle fibres were multiply innervated, and if any of the nerve-muscle contacts were non-synaptic. 2. Synaptic potentials evoked by electrical stimulation of a ganglion were graded with stimulus strength. When two ganglia were plated near each other, synaptic potentials could be evoked in some muscle fibres by stimulation of either ganglion. These observations suggest that muscle fibres were multiply innervated. 3. Spontaneous synaptic potentials recorded from single muscle fibres with two widely spaced micropipettes varied in a manner which suggested that the synapses were distributed at different points on the surface of the muscle fibres. 4. Stimulation of some nerve processes failed to evoke synaptic potentials in muscle fibres contacted by those processes. Such nerve-muscle contacts were not strongly adhesive, and the nerves were peeled easily from the surface of the muscle with a micropipette. On the other hand, nerve processes which formed synaptic contacts with muscle fibres seemed to be tightly adherent to the muscle. 5. Electron microscopic observations of nerve-muscle contacts revealed that the vast majority of such contacts lacked morphological specializations characteristic of mature neuromuscular synapses.

Animals↗
PubMed1969

Correlation between transmission and structure in avian ciliary ganglion synapses.

1. Extracellular responses from post-ganglionic axons of pigeon and chick isolated ciliary ganglia were elicited by stimulation of the presynaptic nerve. Intracellular recordings were also obtained from newly hatched pigeon and chick ganglion cells. The fine structure of ganglia from pigeons of various ages was examined with the electron microscope.2. In ganglia from chick embryos and pigeons up to 10 days old, the extracellular response was unimodal with a long latency and could be blocked by the addition of D-tubocurarine (D-TC) or hexamethonium to the bathing solution. A bimodal extracellular response appeared in pigeons about 10 days after hatching. Only the second peak of the response could be blocked by D-TC or hexamethonium. The response recorded from 22 to 26-day-old pigeons was similar to that seen in the adult.3. The intracellular recordings from ganglion cells of 2-week-old pigeons exhibit two post-synaptic potentials elicited by presynaptic stimulation. The first post-synaptic potential appears to be due to current flow through the ganglion cell during the presynaptic action potential. The second is chemically mediated. In pigeons from 1 to 6 days old, only the second post-synaptic potential is observed.4. The presynaptic terminals in the 4-day-old birds were in the form of calyces. In pigeons 7 days old or older, boutons appeared. The boutons were presumably formed as a result of cleavage of calyciform nerve terminals. Myelin was seen first in the 7-day-old pigeon, was well developed in the 16-day-old bird, and persisted in the adults.5. In adult ganglia, the first component of the extracellular response decreased and was finally abolished after 10-12 hr of superfusion with Tyrode solution. The second component of the response increased concomitantly. The only anatomical change noted in the ganglia after soaking was the disruption and separation of the myelin lamellae from each other and from around the ganglion and presynaptic terminals.6. It is concluded that the myelin is necessary for electrical transmission in the pigeon ciliary ganglion.

Age Factors↗
PubMed1993

Subthreshold oscillations of the membrane potential: a functional synchronizing and timing device.

1. Subthreshold membrane potential oscillations have been observed in different types of CNS neurons. In this in vitro study, we examined the possible role of these oscillations by analyzing the responses of neurons from the inferior olivary nucleus to a combined stimulation of sine wave and synaptic potentials. 2. A nonlinear summation of the sine wave and the synaptic potential occurred in olivary neurons; a superlinear summation occurred when the synaptic potential was elicited at the trough of the sine wave or during the rising phase. On the other hand, a less than linear summation occurred when the synaptic potentials were evoked during the falling phase of the wave. 3. Significant changes in the delay of the synaptic responses were observed. As a result of these changes, the maximum amplitude of the response occurred at the peak of the sine wave, regardless of the exact time of stimulation. The output of the neuron was therefore synchronized with the sine wave and depended only partly on the input phase. 4. These data demonstrate that neurons from the inferior olivary nucleus are capable of operating as accurate synchronizing devices. Moreover, by affecting the delay line, they act as a logic gate that ensures that the information will be added to the system only at given times.

Animals↗
PubMed2006

Dopamine selectively potentiates hippocampal mossy fiber to CA3 synaptic transmission.

Dopamine has been implicated in various brain functions and the pathology of neurological diseases. In the hippocampus, dopamine has been shown to induce acute depression of synaptic transmission in the CA1 region, but it remains largely unknown how it works in the CA3 region. We here report that dopamine induces acute synaptic potentiation at the synapse formed by mossy fibers (MFs) on mouse hippocampal CA3 pyramidal cells, but not at converging associational/commissural synapses. Dopamine potentiated both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) components of MF synaptic responses similarly in respect of the magnitude and time course. The dopamine-induced potentiation was intact in the presence of picrotoxin, required activation of D(1)-like receptors and was apparently occluded by an activator of adenylate cyclase. The potentiation was accompanied by a decrease in magnitude of synaptic facilitation, suggesting the presynaptic site for the expression of the potentiation. The present study is the first demonstration of acute potentiation of hippocampal excitatory synaptic transmission by dopamine, which is most probably mediated by presynaptic D(1)-like receptor-cAMP cascades.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1968

Reticulospinal inhibition of interneurones.

1. The effect of electrical stimulation of the brain stem on interneurones in the dorsal horn and intermediary region has been investigated in decerebrate cats after partial transection of the spinal cord.2. Stimuli that effectively depress reflex transmission without giving a primary afferent depolarization inhibit the discharge evoked from the flexor reflex afferents in interneurones.3. Brain stem stimulation did not give post-synaptic potentials in the great majority of interneurones but effectively depressed the excitatory post-synaptic potentials (EPSPs) and inhibitory post-synaptic potentials (IPSPs) evoked from the flexor reflex afferents in these interneurones.4. IPSPs were, however, evoked in five of seventy-eight intracellularly recorded interneurones. These five interneurones were monosynaptically activated from primary afferents.5. It is tentatively postulated that a dorsal reticulospinal system inhibits reflex transmission by giving post-synaptic inhibition in first order interneurones. The results are also discussed in relation to effects on interneurones from other descending pathways.

Animals↗
PubMed2003

The induction of long-term potentiation at amygdalo-hippocampal synapses in vivo.

Electrical stimulation of the basolateral amygdala (BLA) evoked synaptic potentials in the dentate gyrus (DG) of the hippocampus in anesthetized rats. To determine if this pathway possesses synaptic plasticity, we investigated the impact of several conditions of high-frequency stimulation on BLA-DG synaptic potentials in these rats. Application of two trains of 100-pulse, 100-Hz stimulation or theta-burst stimulation to the BLA reproducibly induced long-term potentiation (LTP) of BLA-DG synaptic potentials. Paired-pulse facilitation was unchanged during LTP, suggesting that postsynaptic mechanisms are involved in the expression of LTP. In addition, the induction of LTP was not affected by the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate, suggesting that activation of NMDA receptors is not required. This novel form of LTP should be a valuable model for elucidating neural mechanisms underlying the formation of emotional memory.

Amygdala↗
PubMed1984

Physiological evidence for specificity of synaptic connections between individual sensory and motor neurons in the brachial spinal cord of the bullfrog.

We have studied synaptic connections between individual stretch-sensitive muscle afferents and motoneurons in the brachial spinal cord of bullfrogs. Sensory afferents from a given head of the triceps brachii muscle preferentially innervate motoneurons that project to the same muscle head. This preference is characterized in two ways: each class of sensory axon innervates a greater proportion of corresponding motoneurons than of motoneurons projecting to synergistic or unrelated muscles, and the synaptic potentials in these corresponding motoneurons are motoneurons that project to the same muscle head. This preference is characterized in two ways: each class of sensory axon innervates a greater proportion of corresponding motoneurons than of motoneurons projecting to synergistic or unrelated muscles, and the synaptic potentials in these corresponding motoneurons are of larger amplitude. A novel feature of these experiments is that even the smallest averaged synaptic potential is several times larger than the noise level. These smallest synaptic potentials thus represent the smallest synaptic interaction between a sensory and motor cell, and they could be the physiological correlate of a single sensory bouton on a motoneuronal dendrite.

Animals↗
PubMed1986

Lamina VIII interneurones interposed in crossed reflex pathways in the cat.

The location of a group of interneurones projecting to contralateral motor nuclei has been established using retrograde transneuronal transport of horseradish peroxidase conjugated with wheat germ agglutinin (WGA-HRP). After labelling the motoneurones of semitendinosus, medial gastrocnemius or quadriceps muscles, interneurones which were secondarily labelled were found in lamina VIII and in the neighbouring narrow strip of lamina VII. They were found to be distributed from the 4th lumbar to the 1st sacral segments, with the highest concentration in the 6th and 7th lumbar segments and at the border between the 4th and 5th lumbar segments. The electrophysiological properties of lamina VIII interneurones of the 6th lumbar segment have been investigated using both extracellular and intracellular recording. Many of these interneurones could be antidromically activated following weak stimuli applied in contralateral motor nuclei. Post-synaptic potentials were evoked from a variety of primary afferents including group I muscle afferents. However, when present, the post-synaptic potentials (p.s.p.s) of group I origin were of considerably smaller amplitudes than p.s.p.s. evoked from higher threshold muscle or cutaneous afferents and smaller than p.s.p.s. which followed stimulation of the spinal cord at the thoracic level. P.s.p.s. from the latter two sources appear to constitute the main input to lamina VIII interneurones. Group I input has been found in forty lamina VIII interneurones. These were usually affected by either ipsilateral or contralateral group I afferents and only exceptionally by both. Excitatory post-synaptic potentials (e.p.s.p.s) from ipsilateral afferents were evoked in about twice as many neurones as e.p.s.p.s from the contralateral afferents. E.p.s.p.s were often accompanied by inhibitory post-synaptic potentials (i.p.s.p.s). Group Ia afferents appeared to contribute to both e.p.s.p.s and i.p.s.p.s, whether these were evoked from ipsilateral or from contralateral afferents. In several cases Ia afferents were as effective as all group I afferents while in other cases Ib afferents appeared to be an important or even the exclusive source of the p.s.p.s. The latencies of e.p.s.p.s indicated that they were evoked mono-, di- or trisynaptically from ipsilateral group I afferents and di- or trisynaptically from contralateral afferents, I.p.s.p.s appeared to be evoked via pathways with only one additional interneurone. About one-third of all the intracellularly investigated lamina VIII interneurones were both affected by group I afferents and antidromically activated from the contralateral motor nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1998

Crocin antagonizes ethanol inhibition of NMDA receptor-mediated responses in rat hippocampal neurons.

We have previously found that crocin (crocetin di-gentiobiose ester) antagonizes the inhibitory effect of ethanol on long-term potentiation in the rat hippocampus in vivo and in vitro. To explore mechanisms underlying the antagonism of crocin against ethanol, we investigated the effects of ethanol and crocin on synaptic potentials mediated by N-methyl-d-aspartate (NMDA) receptors in the dentate gyrus of rat hippocampal slices. Synaptic potential mediated by non-NMDA receptors was recorded in normal medium (1.3 mM Mg2+), while NMDA receptor-mediated synaptic potential was isolated in low (0.13 mM) Mg2+ medium containing the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM). Crocin (10 microM) alone did not affect synaptic potentials mediated by non-NMDA nor NMDA receptors. Non-NMDA response was slightly inhibited by 100 mM ethanol, while NMDA response was selectively inhibited by lower concentrations (10-50 mM) of ethanol. Crocin (10 microM) did not affect the inhibition of non-NMDA response by 100 mM ethanol, but significantly blocked the inhibition of NMDA response by 10-50 mM ethanol. In addition, we performed whole-cell patch recording with primary cultured rat hippocampal neurons, and confirmed that crocin blocked ethanol inhibition of inward currents evoked by application of NMDA. These results suggest that crocin specifically antagonizes the inhibitory effect of ethanol on NMDA receptor-mediated responses in hippocampal neurons.

Animals↗
PubMed1982

Mechanism of inhibition by the amygdala in the lateral hypothalamic area of rats.

The inhibition of neuronal activity in the lateral hypothalamus (LHA) of the rat by the basolateral nucleus of the amygdala (AL) was investigated by analyzing evoked potentials, single unit discharges and intracellular synaptic potentials. A single volley to the AL induced a negative-positive-wave in the LHA. The negative-wave threshold was lower than that of the positive wave. Analysis of depth profiles showed that the negative- and positive-waves appeared first at the dorsal margin of the LHA, peaked within the LHA, and were clearly different from each other. The effects of acute lesions showed the negative-wave to be conducted through the direct amygdalo-hypothalamic pathway. The positive-wave: through the stria terminalis. Stimulation of the stria terminalis produced positive evoked potentials with latencies shorter than those of the positive-waves. When conditioning and test stimuli were delivered to the AL, the negative-wave was inhibited for about 90 msec by the evoked positive-wave. Single AL stimuli evoked single unit discharges followed by inhibition of spontaneous firing for about 100 msec. Single stria terminalis stimuli inhibited spontaneous firing for the duration of the positive evoked potential. Intracellular LHA recording during single AL stimuli showed the presence of an EPSP followed by a 100 msec long lasting IPSP. The negative and positive extracellular potentials corresponded to these synaptic potentials. Inward current injection of 1 to 1.4 nA reversed the IPSP's indicating a -15 mV hyperpolarization difference between the IPSP reversal potential and the resting potential in LHA cells. The ionic mechanism of the IPSP is also discussed.

Amygdala↗
PubMed1984

Crossed actions of group I muscle afferents in the cat.

Reflex actions evoked by electrical stimulation of contralateral quadriceps, hamstring and gastrocnemius-soleus muscle afferents were investigated using intracellular recording from motoneurones, in chloralose-anaesthetized, acute, low spinal cats. Contralateral group I afferents were found to evoke excitatory post-synaptic potentials only occasionally. Contralateral group II afferents evoked post-synaptic potentials (excitatory to extensor motoneurones and inhibitory to flexor motoneurones) from the quadriceps nerve, whereas contralateral group III afferents evoked post-synaptic potentials (with the same pattern as quadriceps group II) from all muscles tested. Contralateral group I afferents were found to facilitate Ia reciprocal inhibition, and both the excitatory and inhibitory reflex actions from Ib afferents. This is taken to indicate an action of these afferents on interneurones interposed in ipsilateral reflex pathways.

Action Potentials↗
PubMed1995

Endogenous opioids regulate long-term potentiation of synaptic inhibition in the dentate gyrus of rat hippocampus.

Long-term potentiation (LTP) of excitatory transmission in the hippocampus has been extensively studied as a synaptic model of learning and memory. Here we report a new form of LTP in which inhibitory synaptic signals are potentiated following tetanic stimulation of an opioid-containing excitatory pathway in the presence of opioid antagonists. The lateral perforant path (LPP) was stimulated at the dentate outer molecular layer of hippocampal slices. Evoked synaptic currents were recorded from dentate granule cells using whole-cell voltage-clamp techniques. A high-frequency stimulus train (100 Hz, 1 sec) delivered to the LPP in the presence of naloxone (1 microM) was found to induce a long-lasting potentiation (20 min to 2 hr) in the amplitude of gamma-aminobutyric acidA (GABAA) receptor-mediated inhibitory postsynaptic currents (IPSCs) of granule cells. Such a potentiation was not observed when tetanizing the LPP in control medium. Naloxone-revealed LTP of LPP-evoked IPSCs did not depend upon the presence of granule cell discharge, and was not accompanied by potentiation of mossy fiber-evoked IPSCs, indicating that feedforward, but not feedback, inhibitory circuits were involved. Induction of this LTP could be completely blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoic acid (D-APV). However, it was not significantly affected by hyperpolarization of granule cells. These results suggest that LTP may occur at the excitatory synapses between LPP terminals and GABAergic interneurons, rather than at the inhibitory synapses between interneurons and granule cells. Further examination using selective opioid antagonists demonstrated that blocking delta, but not mu and kappa, receptors is critical for inducing LTP of IPSCs in granule cells.

2-Amino-5-phosphonovalerate↗
PubMed1988

Analysis of effective synaptic currents generated by homonymous Ia afferent fibers in motoneurons of the cat.

1. We have developed a technique to measure the total amount of current from a synaptic input system that reaches the soma of a motoneuron under steady-state conditions. We refer to this quantity as the effective synaptic current (IN) because only that fraction of the synaptic current that actually reaches the soma and initial segment of the cell affects its recruitment threshold and firing frequency. 2. The advantage of this technique for analysis of synaptic inputs in comparison to the standard measurements of synaptic potentials is apparent from Ohm's law. Steady-state synaptic potentials recorded at the soma of a cell are the product of IN and input resistance (RN), which is determined by intrinsic cellular properties such as cell size and membrane resistivity. Measuring IN avoids the confounding effect of RN on the amplitudes of synaptic potentials and thus provides a more direct assessment of the magnitude of a synaptic input. 3. Steady-state synaptic inputs were generated in cat medial gastrocnemius (MG) motoneurons by using tendon vibration to activate homonymous Ia afferents. We found that the magnitude of the Ia effective synaptic current (Ia IN) was not the same in all MG cells. Instead, Ia IN covaried with RN (r = 0.64; P less than 0.001), being about twice as large on average in motoneurons with high RN values as in those with low RN values. Ia IN was also correlated with motoneuron rheobase, afterhyperpolarization duration, and axonal conduction velocity. 4. A comparison of transient Ia EPSPs with steady-state Ia EPSPs (Ia EPSPSS) evoked in the same cells suggested that the effective synaptic current that produces the transient Ia EPSP was also greater in motoneurons with high RN values than in those with low RN values. 5. The factors responsible for the Ia IN-RN covariance are uncertain. However, our finding greater values of Ia IN in high RN motoneurons is consistent with other evidence suggesting that Ia boutons on these motoneurons have a higher probability for neurotransmitter release than those on low RN motoneurons (19). 6. The neural mechanisms underlying orderly recruitment are discussed. The effect of the Ia input is to produce an approximately twofold expansion of the differences in motoneuron recruitment thresholds that are generated by intrinsic cellular properties. It is suggested that the higher efficacy of Ia input in low-threshold motoneurons confers particular importance on this input system in the control of vernier movements (7).

Afferent Pathways↗
PubMed2000

BDNF-Induced potentiation of spontaneous twitching in innervated myocytes requires calcium release from intracellular stores.

Brain-derived neurotrophic factor (BDNF) can potentiate synaptic release at newly developed frog neuromuscular junctions. Although this potentiation depends on extracellular Ca(2+) and reflects changes in acetylcholine release, little is known about the intracellular transduction or calcium signaling pathways. We have developed a video assay for neurotrophin-induced potentiation of myocyte twitching as a measure of potentiation of synaptic activity. We use this assay to show that BDNF-induced synaptic potentiation is not blocked by cadmium, indicating that Ca(2+) influx through voltage-gated Ca(2+) channels is not required. TrkB autophosphorylation is not blocked in Ca(2+)-free conditions, indicating that TrkB activity is not Ca(2+) dependent. Additionally, an inhibitor of phospholipase C interferes with BDNF-induced potentiation. These results suggest that activation of the TrkB receptor activates phospholipase C to initiate intracellular Ca(2+) release from stores which subsequently potentiates transmitter release.

Action Potentials↗
PubMed1987

Potentiation of enkephalin action by peptidase inhibitors in rat locus ceruleus in vitro.

Intracellular recordings were made from locus ceruleus (LC) neurons in slices of rat pons. It has been shown previously that opioids inhibit firing and hyperpolarize LC neurons by activating mu-opioid receptors. Concentration-response curves were constructed by measuring the hyperpolarization, or outward current at -60 mV, caused by various opioid agonists added to the superfusing solution. Peptidase inhibitors (kelatorphan, bestatin and thiorphan) each increased the potency of Met-enkephalin, Leu-enkephalin and metorphamide but had no effect of their own on the LC neurons. Kelatorphan (20 microM) produced a 7-fold shift to the left of the Met-enkephalin dose-response curve. Higher concentrations produced no further shift. Thiorphan (3 microM) and bestatin (20 microM) each had a smaller potentiating effect on the Met-enkephalin hyperpolarization. The effects of Tyr-D-Ala-Gly-MePhe-Gly-ol and noradrenaline were not potentiated by these peptidase inhibitors. Electrical stimulation produced an inhibitory synaptic potential that was prolonged by cocaine (10 microM) and blocked by the alpha-2 adrenoceptor antagonist idazoxan (1 microM). After addition of idazoxan, hyperpolarizing synaptic potentials could be evoked even in the presence of kelatorphan (20 microM). These results indicate that peptide metabolism in the intact brain slice can account for a substantial decrease in the sensitivity of LC neurons to exogenously applied opioid peptides; even after peptidase inhibition, no evidence could be obtained for hyperpolarizing synaptic potentials due to the release of endogenous opioids.

Analgesics↗
PubMed2006

Role of the neurogranin concentrated in spines in the induction of long-term potentiation.

Synaptic plasticity in CA1 hippocampal neurons depends on Ca2+ elevation and the resulting activation of calmodulin-dependent enzymes. Induction of long-term depression (LTD) depends on calcineurin, whereas long-term potentiation (LTP) depends on Ca2+/calmodulin-dependent protein kinase II (CaMKII). The concentration of calmodulin in neurons is considerably less than the total concentration of the apocalmodulin-binding proteins neurogranin and GAP-43, resulting in a low level of free calmodulin in the resting state. Neurogranin is highly concentrated in dendritic spines. To elucidate the role of neurogranin in synaptic plasticity, we constructed a computational model with emphasis on the interaction of calmodulin with neurogranin, calcineurin, and CaMKII. The model shows how the Ca2+ transients that occur during LTD or LTP induction affect calmodulin and how the resulting activation of calcineurin and CaMKII affects AMPA receptor-mediated transmission. In the model, knockout of neurogranin strongly diminishes the LTP induced by a single 100 Hz, 1 s tetanus and slightly enhances LTD, in accord with experimental data. Our simulations show that exchange of calmodulin between a spine and its parent dendrite is limited. Therefore, inducing LTP with a short tetanus requires calmodulin stored in spines in the form of rapidly dissociating calmodulin-neurogranin complexes.

Calcium↗