Long-term Changes In Neuronal Excitability Research Articles

TGF-β1-Induced Long-Term Changes in Neuronal Excitability inAplysiaSensory Neurons Depend on MAPK

Transforming growth factor beta-1 (TGF-beta1) plays important roles in the early development of the nervous system and has been implicated in neuronal plasticity in adult organisms. It induces long-term increases in sensory neuron excitability in Aplysia as well as a long-term enhancement of synaptic efficacy at sensorimotor synapses. In addition, TGF-beta1 acutely regulates synapsin phosphorylation and reduces synaptic depression induced by low-frequency stimuli. Because of the critical role of MAPK in other forms of long-term plasticity in Aplysia, we examined the role of MAPK in TGF-beta1-induced long-term changes in neuronal excitability. Prolonged (6 h) exposure to TGF-beta1 induced long-term increases in excitability. We confirmed this finding and now report that exposure to TGF-beta1 was sufficient to activate MAPK and increase nuclear levels of active MAPK. Moreover, TGF-beta1 enhanced phosphorylation of the Aplysia transcriptional activator cAMP response element binding protein (CREB)1, a homologue to vertebrate CREB. Both the TGF-beta1-induced long-term changes in neuronal excitability and the phosphorylation of CREB1 were blocked in the presence of an inhibitor of the MAPK cascade, confirming a role for MAPK in long-term modulation of sensory neuron function.

Localization of the A kinase anchoring protein AKAP79 in the human hippocampus.

The phosphorylation state of the proteins, regulated by phosphatases and kinases, plays an important role in signal transduction and long-term changes in neuronal excitability. In neurons, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and calcineurin (CN) are attached to a scaffold protein, A kinase anchoring protein (AKAP), thought to anchor these three enzymes to specific sites of action. However, the localization of AKAP, and the predicted sites of linked phosphatase and kinase activities, are still unknown at the fine structural level. In the present study, we investigated the distribution of AKAP79 in the hippocampus from postmortem human brains and lobectomy samples from patients with intractable epilepsy, using preembedding immunoperoxidase and immunogold histochemical methods. AKAP79 was found in the CA1, presubicular and subicular regions, mostly in pyramidal cell dendrites, whereas pyramidal cells in the CA3, CA2 regions and dentate granule cells were negative both in postmortem and in surgical samples. In some epileptic cases, the dentate molecular layer and hilar interneurons also became immunoreactive. At the subcellular level, AKAP79 immunoreactivity was present in postsynaptic profiles near, but not attached to, the postsynaptic density of asymmetrical (presumed excitatory) synapses. We conclude that the spatial selectivity for the action of certain kinases and phosphatases regulating various ligand- and voltage-gated channels may be ensured by the selective presence of their anchoring protein, AKAP79, at the majority of glutamatergic synapses in the CA1, but not in the CA2/CA3 regions, suggesting profound differences in signal transduction and long-term synaptic plasticity between these regions of the human hippocampus.

Long-term changes in sciatic-evoked A-fiber dorsal horn field potentials accompany loose ligation of the sciatic nerve in rats

The goal of the present study was to examine whether loose ligation of the sciatic nerve was associated with long-term changes in neuronal excitability in the spinal dorsal horn in urethane-anesthetized rats. The sciatic nerve was stimulated with 0.1 ms long pulses at 1 stimulus/5 min, and the evoked dorsal horn field potentials remained stable in the absence of tetanic stimulation. In one set of control and ligated animals, high-frequency tetanic stimulation was applied to the nerve at 50 Hz (one 400 ms train of twenty 0.1 ms pulses), and the field potentials were recorded again (1 stimulus/5 min) for up to 4 h post-tetanus. In control animals, this protocol produced significant increases in field potential amplitudes at 15, 30 and 60 min post-tetanus. Interestingly, after this time the evoked field potentials began to decrease, and attained less than 50% of their pre-tetanic values at 240 min post-tetanus. In contrast, in ligated rats the pattern of post-tetanic potentiation was significantly different as the increases in amplitude persisted, and at 240 min post-tetanus the field potentials were almost twice their baseline values.In another set of control and ligated animals, low-frequency tetanic stimulation was applied at 5 Hz (one 400 ms train of two 0.1 ms pulses). Again a differential pattern of post-tetanic responses between control and ligated rats was seen. In control animals, a significant decrease in amplitude was evident within 30 min, and the depression became progressively more pronounced as the field potentials attained about a quarter of their baseline values at 180 min, and remained at these low levels at 240 min post-tetanus. On the other hand, in ligated animals, the depression was not significant, and at 240 min post-tetanus the field potentials were still at about 80% of their baseline values.These data demonstrate that long-term changes in spinal dorsal horn neuronal excitability accompany sciatic ligation to perhaps contribute to the development of neuropathic pain. These changes may result from a lessening of normally strong inhibitory processes in the spinal dorsal horn to generate conditions which favor post-tetanic potentiation over depression of dorsal horn neuronal responses.

Heterologous Expression of the Kv3.1 Potassium Channel Eliminates Spike Broadening and the Induction of a Depolarizing Afterpotential in the Peptidergic Bag Cell Neurons

The bag cell neurons of Aplysia are a cluster of cells that control egg laying behavior. After brief synaptic stimulation, they depolarize and fire spontaneously for up to 30 min. During the first few seconds of this afterdischarge, the action potentials of the bag cell neurons undergo pronounced broadening. Single bag cell neurons in culture also show spike broadening in response to repeated depolarizations. This broadening is frequency-dependent and associated with the induction of a depolarizing afterpotential lasting minutes. In some neurons the depolarizing afterpotential is sufficient to trigger spontaneous firing. To test the possibility that spike broadening during stimulation is required to trigger the depolarizing afterpotential, we eliminated frequency-dependent broadening by heterologous expression of the Kv3.1 potassium channel. This channel has rapid activation and deactivation kinetics and no use-dependent inactivation. Expression of Kv3.1 prevented spike broadening and also eliminated the depolarizing afterpotential. Measurements of the integral of calcium current during voltage commands, which simulated the action potentials of the control neurons and those expressing Kv3.1, indicate that spike broadening produces up to a fivefold increase in calcium entry. Manipulations that limit calcium entry during action potentials or chelation of intracellular calcium using BAPTA AM prevented the induction of the depolarizing afterpotential. We conclude that spike broadening is essential for the induction of the depolarizing afterpotential probably by regulating calcium influx and suggest that one of the physiological roles of spike broadening may be to regulate long-term changes in neuronal excitability.

Free Radicals, Calcium., and The Synaptic Plasticity-Cell Death Continuum: Emerging Roles of The Transcription Factor Nfκb

Publisher Summary Neurotransmitters, neurotrophic factors, cytokines, and cell adhesion molecules are among the categories of intercellular signals that play major roles in regulating neurite outgrowth, synaptogenesis, and synaptic plasticity. The central role of calcium and oxy radicals in orchestrating various adaptive responses of neurons probably arises from the fact that multicellular organisms evolved in an oxidizing environment and under conditions of ionic turmoil. Calcium influx regulates growth cone behavior by controlling the state of polymerization of microfilaments and microtubules, the cytoskeletal underpinnings of filipodial movements and neurite elongation, respectively. Learning and memory are encoded by signaling processes initiated at synapses that are transduced into long-term changes in neuronal excitability. Induction of gene expression appears to be involved in maintenance of the strengthening of synaptic connections in paradigms of learning and memory. Research findings suggest that the NF K B plays an important role in transducing calcium and ROS synaptic signals into genetic responses. NF K B is a cytosolic transcription factor that can be activated in response to synaptic activity. This provides a mechanism of synapse-to-nucleus signaling that plays an important role in activity-dependent long-lasting changes in neuronal structure and function. NF K B also appears to play an important role in the adaptive responses of neurons to potentially lethal excitotoxic, metabolic, and oxidative insults. NF K B induces the expression of genes encoding cytoprotective proteins, including those that suppress the accumulation of ROS, for example, manganese superoxide dismutase, and stabilize calcium homeostasis, for example the calcium-binding protein calbindin.

Protein kinase C activation induces conductance changes in Hermissenda photoreceptors like those seen in associative learning

Phosphorylation of ion channels has been suggested as one molecular mechanism responsible for learning-produced long-term changes in neuronal excitability. Persistent training-produced changes in two distinct K+ currents (IA (ref. 2), IK-Ca (refs 3,4)) and a voltage-dependent calcium current (ICa; refs 3,4) have previously been shown to occur in type B photoreceptors of Hermissenda, as a result of associative learning. But the identity of the phosphorylation pathway(s) responsible for these changes has not as yet been determined. Injections of cyclic AMP-dependent protein kinase reduce a K+ current (IK) in B cells which is different from those changed by training, but fails to reduce IA and IK-Ca. Phosphorylase b kinase (an exogenous calcium/calmodulin-dependent kinase) reduces IA, but whether IK-Ca and ICa are changed in the manner of associative training is not yet known. Another protein kinase present in high concentrations in both mammalian brain and molluscan nervous systems is protein kinase C, which is both calcium- and phospholipid-sensitive. We now present evidence that activation of protein kinase C by the tumour promoter phorbol ester (PDB) and intracellular injection of the enzyme induce conductance changes similar to those caused by associative training in Hermissenda B cells (that is a reduction of IA and IK-Ca, and enhancement of ICa). These results represent the first direct demonstration that protein kinase C affects membrane K+ ion conductance mechanisms.

Kindling induces long-lasting alterations in response of hippocampal neurons to elevated potassium levels in vitro.

The cellular basis of kindling was studied electrophysiologically with slices of guinea pig hippocampus. Normally, epileptiform activity can be induced in the slices only by combined exposure to elevated potassium levels and a chemical convulsant such as penicillin. In hippocampal slices from pentylenetetrazole-kindled animals, however, elevated potassium alone can induce seizures. These data suggest that kindling elicits long-term changes in neuronal excitability that may involve ionic mechanisms.

Kindling as a Model for Alcohol Withdrawal Syndromes

Periodic brain stimulation, particularly in the limbic system, at stimulus intensities initially too low to produce any behavioural or EEG effects, progressively produces EEG changes, motor automatisms, and eventually convulsions, an effect called kindling. Data are presented and reviewed that suggest that the severity of alcohol withdrawal symptoms progressively increases over years of alcohol abuse in a stepwise fashion similar to the kindling process. The model is presented that the limbic system hyperirritability which accompanies each alcohol withdrawal serves over time to kindle increasingly widespread subcortical structures. These long-term changes in neuronal excitability might relate to the progression of alcohol withdrawal symptoms from tremor to seizures and delirium tremens, as well as the alcoholic personality changes between episodes of withdrawal.