Synaptic depression creates a switch that controls the frequency of an oscillatory circuit.
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Synaptic depression is a form of short-term plasticity exhibited by many synapses. Nonetheless, the functional significance of synaptic depression in oscillatory networks is not well understood. We show that, in a recurrent inhibitory network that includes an intrinsic oscillator, synaptic depression can give rise to two distinct modes of network operation. When the maximal conductance of the depressing synapse is small, the oscillation period is determined by the oscillator component. Increasing the maximal conductance beyond a threshold value activates a positive-feedback mechanism that greatly enhances the synaptic strength. In this mode, the oscillation period is determined by the strength and dynamics of the depressing synapse. Because of the regenerative nature of the feedback mechanism, the circuit can be switched from one mode of operation to another by a very small change in the maximal conductance of the depressing synapse. Our model was inspired by experimental work on the pyloric network of the lobster. The pyloric network produces a simple motor rhythm generated by a pacemaker neuron that receives feedback inhibition from a depressing synapse. In some preparations, elimination of the synapse had no effect on the period of the rhythm, whereas in other preparations, there was a significant decrease in the period. We propose that the pyloric network can operate in either of the two modes suggested by the model, depending on the maximal conductance of the depressing synapse. (+info)
latheo, a Drosophila gene involved in learning, regulates functional synaptic plasticity.
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Mutations in the latheo (lat) gene disrupt associative learning in Drosophila , but a role for LAT in regulating neuronal function has not been demonstrated. Here, we report that LAT plays a central role in regulating Ca2(+)- and activity-dependent synaptic plasticity. Immunological localization of the LAT protein indicates it is present at synaptic connections of the larval neuromuscular junction (NMJ) and is enriched in presynaptic boutons. Basal synaptic transmission amplitude at the lat mutant NMJ is elevated 3- to 4-fold, and Ca2+ dependence of transmission is significantly reduced. Multiple forms of synaptic facilitation and posttetanic potentiation (PTP) are strongly depressed or absent at the mutant synapse. Our results suggest that LAT is a novel presynaptic protein with a role in the Ca2(+)-dependent synaptic modulation mechanisms necessary for behavioral plasticity. (+info)
Rabphilin knock-out mice reveal that rabphilin is not required for rab3 function in regulating neurotransmitter release.
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Rab3A and rab3C are GTP-binding proteins of synaptic vesicles that regulate vesicle exocytosis. Rabphilin is a candidate rab3 effector at the synapse because it binds to rab3s in a GTP-dependent manner, it is co-localized with rab3s on synaptic vesicles, and it dissociates with rab3s from the vesicles during exocytosis. Rabphilin contains two C(2) domains, which could function as Ca(2+) sensors in exocytosis and is phosphorylated as a function of stimulation. However, it is unknown what essential function, if any, rabphilin performs. One controversial question regards the respective roles of rab3s and rabphilin in localizing each other to synaptic vesicles: although rabphilin is mislocalized in rab3A knock-out mice, purified synaptic vesicles were shown to require rabphilin for binding of rab3A but not rab3A for binding of rabphilin. To test whether rabphilin is involved in localizing rab3s to synaptic vesicles and to explore the functions of rabphilin in regulating exocytosis, we have now analyzed knock-out mice for rabphilin. Mice that lack rabphilin are viable and fertile without obvious physiological impairments. In rabphilin-deficient mice, rab3A is targeted to synaptic vesicles normally, whereas in rab3A-deficient mice, rabphilin transport to synapses is impaired. These results show that rabphilin binds to vesicles via rab3s, consistent with an effector function of rabphilin for a synaptic rab3-signal. Surprisingly, however, no abnormalities in synaptic transmission or plasticity were observed in rabphilin-deficient mice; synaptic properties that are impaired in rab3A knock-out mice were unchanged in rabphilin knock-out mice. Our data thus demonstrate that rabphilin is endowed with the properties of a rab3 effector but is not essential for the regulatory functions of rab3 in synaptic transmission. (+info)
Repetitive activation of corticostriatal fibers produces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of synaptic plasticity might be considered the possible neural basis of some forms of motor learning and memory. In the present study, intracellular recordings were performed from rat corticostriatal slice preparations to study the role of glutamate and other critical factors underlying striatal LTD. In current-clamp, but not in voltage-clamp experiments, brief focal applications of glutamate, as well as high-frequency stimulation (HFS) of corticostriatal fibers, induced LTD. This pharmacological LTD and the HFS-induced LTD were mutually occlusive, suggesting that both forms of synaptic plasticity share common induction mechanisms. Isolated activation of either non-NMDA-ionotropic glutamate receptors (iGluRs) or metabotropic glutamate receptors (mGluRs), respectively by AMPA and t-ACPD failed to produce significant long-term changes of corticostriatal synaptic transmission. Conversely, LTD was obtained after the simultaneous application of AMPA plus t-ACPD. Moreover, also quisqualate, a compound that activates both iGluRs and group I mGluRs, was able to induce this form of pharmacological LTD. Electrical depolarization of the recorded neurons either alone or in the presence of t-ACPD and dopamine (DA) failed to mimic the effects of the activation of glutamate receptors in inducing LTD. However, electrical depolarization was able to induce LTD when preceded by coadministration of t-ACPD, DA, and a low dose of hydroxylamine, a compound generating nitric oxide (NO) in the tissue. None of these compounds alone produced LTD. Glutamate-induced LTD, as well as the HFS-induced LTD, was blocked by L-sulpiride, a D2 DA receptor antagonist, and by 7-nitroindazole monosodium salt, a NO synthase inhibitor. The present study indicates that four main factors are required to induce corticostriatal LTD: (1) membrane depolarization of the postsynaptic neuron; (2) activation of mGluRs; (3) activation of DA receptors; and (4) release of NO from striatal interneurons. (+info)
Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits.
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Febrile (fever-induced) seizures affect 3-5% of infants and young children. Despite the high incidence of febrile seizures, their contribution to the development of epilepsy later in life has remained controversial. Combining a new rat model of complex febrile seizures and patch clamp techniques, we determined that hyperthermia-induced seizures in the immature rat cause a selective presynaptic increase in inhibitory synaptic transmission in the hippocampus that lasts into adulthood. The long-lasting nature of these potent alterations in synaptic communication after febrile seizures does not support the prevalent view of the 'benign' nature of early-life febrile convulsions. (+info)
Serotonin neurons, neuroplasticity, and homeostasis of neural tissue.
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Homeostasis is the process by which the internal milieu of the body is able to maintain equilibrium in the face of constant insults from the external world. Endocrine, immune, and vascular systems play pivotal roles in adjusting internal biochemical reactions to counteract assaults from the outside. Despite the vast accumulation of data over the last 50 years, a role for serotonin in brain homeostasis has not been proposed. In this chapter I will review the plasticity and anatomy of serotonergic neurons in integrating external sensory and motor systems as well as internal endocrine, glial and vascular signals with the various cellular elements comprising neural tissue. Steroids and neuropeptides have both been shown to alter the morphology of serotonergic neurons. In turn, alterations in serotonin levels in the adult brain can change the morphology of its target cells. A pivotal role for serotonin in the homeostasis of neural tissue is consistent with the function of serotonin throughout evolution and explains the large number of biological systems, behavioral activities, and clinical diseases associated with serotonergic neurons. (+info)
Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons.
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Cannabinoids, the active constituents of marijuana, are known to impair learning and memory. Receptors for cannabinoids are highly expressed in the hippocampus, a brain region that is believed to play an important role in certain forms of learning and memory. To investigate the possible contribution of cannabinoid receptor-mediated deficits in hippocampal function to the learning and memory impairments produced by marijuana, we studied the effects of cannabinoid receptor activation on two models of learning and memory, long-term potentiation (LTP) and long-term depression (LTD), in hippocampal slices. Although LTP and LTD of CA1 field potentials were blocked by cannabinoid receptor activation in the presence of Mg(2+), they could be induced after Mg(2+) was removed. Similarly, LTP and LTD of whole-cell EPSCs were unimpaired in the presence of cannabinoid receptor agonist when the postsynaptic membrane was depolarized during the LTP or LTD induction protocol. Cannabinoid receptor activation also reduced EPSCs and enhanced paired-pulse facilitation, while having no effect on the amplitude of spontaneous miniature EPSCs. Finally, as with cannabinoid receptor activation, inhibition of LTP by adenosine receptor activation could be overcome by removal of Mg(2+) or depolarization of the postsynaptic membrane during tetanus. Our results indicate that cannabinoid receptor activation does not directly inhibit the molecular mechanisms responsible for long-term synaptic plasticity but instead impairs LTP and LTD by reducing presynaptic neurotransmitter release to a level below that required to depolarize the postsynaptic membrane to relieve Mg(2+) blockade of NMDA receptors. (+info)
Subtype-dependence of NMDA receptor channel open probability.
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NMDA receptor-mediated calcium transients play a critical role in synaptogenesis, synaptic plasticity, and excitotoxicity. NMDA receptors are heteromeric complexes of NR1A combined with NR2A, NR2B, NR2C, and/or NR2D subunits. The NR2 subunits determine a variety of electrophysiological and pharmacological properties of the NMDA receptor complex. In this report, we provide evidence for the first time that there is also a significant difference in peak channel open probability (P(o)) between NMDA receptors composed of NR1A/NR2A and those of NR1A/NR2B subunits. First, whole-cell patch-clamp recordings from human embryonic kidney (HEK) 293 cells expressing NMDA receptors revealed that NR1A/NR2A-mediated peak current densities are approximately four times larger than those of NR1A/NR2B. We show that this fourfold difference is unlikely caused by differences in receptor surface expression, since these levels were similar for the two subtypes by Western blot analysis. To determine whether P(o) contributed to the difference in peak current densities, we used two different open channel antagonists, MK-801 and 9-aminoacridine, in a variety of experimental paradigms. Our results indicate that peak P(o) is significantly higher (twofold to fivefold) for NR1A/NR2A than NR1A/NR2B, with estimated values of approximately 0.35 and 0.07, respectively. These results suggest that a change in the relative expression levels of NR2A and NR2B can regulate peak amplitude of NMDA receptor-mediated excitatory postsynaptic potentials and therefore may play a role in mechanisms underlying synaptic plasticity. (+info)