Adaptive Neuronal Responses Research Articles

Nonlinear [Ca2+] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca2+Extrusion

Spine Ca2+ triggers the induction of synaptic plasticity and other adaptive neuronal responses. The amplitude and time course of Ca2+ signals specify the activation of the signaling pathways that trigger different forms of plasticity such as long-term potentiation and depression. The shapes of Ca2+ signals are determined by the dynamics of Ca2+ sources, Ca2+ buffers, and Ca2+ extrusion mechanisms. Here we show in rat CA1 pyramidal neurons that plasma membrane Ca2+ pumps (PMCAs) and Na+/Ca2+ exchangers are the major Ca2+ extrusion pathways in spines and small dendrites. Surprisingly, we found that Ca2+ extrusion via PMCA and Na+/Ca2+ exchangers slows in an activity-dependent manner, mediated by intracellular Na+ and Ca2+ accumulations. This activity-dependent depression of Ca2+ extrusion is, in part, attributable to Ca2+-dependent inactivation of PMCAs. Ca2+ extrusion recovers from depression with a time constant of 0.5 s. Depression of Ca2+ extrusion provides a positive feedback loop, converting small differences in stimuli into large differences in Ca2+ concentration. Depression of Ca2+ extrusion produces Ca2+ concentration dynamics that depend on the history of neuronal activity and therefore likely modulates the induction of synaptic plasticity.

Identification of genes co‐upregulated with Arc during BDNF‐induced long‐term potentiation in adult rat dentate gyrus in vivo

Brain-derived neurotrophic factor (BDNF) is a critical regulator of transcription-dependent adaptive neuronal responses, such as long-term potentiation (LTP). Brief infusion of BDNF into the dentate gyrus of adult anesthetized rats triggers stable LTP at medial perforant path-granule synapses that is transcription-dependent and requires induction of the immediate early gene Arc. Rather than acting alone, Arc is likely to be part of a larger BDNF-induced transcriptional program. Here, we used cDNA microarray expression profiling to search for genes co-upregulated with Arc 3 h after BDNF-LTP induction. Of nine cDNAs encoding for known genes and up-regulated more than four-fold, we selected five genes, Narp, neuritin, ADP-ribosylation factor-like protein-4 (ARL4L), TGF-beta-induced immediate early gene-1 (TIEG1) and CARP, for further validation. Real-time PCR confirmed robust up-regulation of these genes in an independent set of BDNF-LTP experiments, whereas infusion of the control protein cytochrome C had no effect. In situ hybridization histochemistry further revealed up-regulation of all five genes in somata of post-synaptic granule cells following both BDNF-LTP and high-frequency stimulation-induced LTP. While Arc synthesis is critical for local actin polymerization and stable LTP formation, several of the co-upregulated genes have known functions in excitatory synaptogenesis, axon guidance and glutamate receptor clustering. These results provide novel insight into gene expression responses underlying BDNF-induced synaptic consolidation in the adult brain in vivo.

Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens.

Psychostimulant-induced alteration of dendritic spines on dopaminoceptive neurons in nucleus accumbens (NAcc) has been hypothesized as an adaptive neuronal response that is linked to long-lasting addictive behaviors. NAcc is largely composed of two distinct subpopulations of medium-sized spiny neurons expressing high levels of either dopamine D1 or D2 receptors. In the present study, we analyzed dendritic spine density after chronic cocaine treatment in distinct D1 or D2 receptor-containing medium-sized spiny neurons in NAcc. These studies made use of transgenic mice that expressed EGFP under the control of either the D1 or D2 receptor promoter (Drd1-EGFP or Drd2-EGFP). After 28 days of cocaine treatment and 2 days of withdrawal, spine density increased in both Drd1-EGFP- and Drd2-EGFP-positive neurons. However, the increase in spine density was maintained only in Drd1-EGFP-positive neurons 30 days after drug withdrawal. Notably, increased DeltaFosB expression also was observed in Drd1-EGFP- and Drd2-EGFP-positive neurons after 2 days of drug withdrawal but only in Drd1-EGFP-positive neurons after 30 days of drug withdrawal. These results suggest that the increased spine density observed after chronic cocaine treatment is stable only in D1-receptor-containing neurons and that DeltaFosB expression is associated with the formation and/or the maintenance of dendritic spines in D1 as well as D2 receptor-containing neurons in NAcc.

Differential Dynamic Plasticity of A1 Receptive Fields during Multiple Spectral Tasks

Auditory experience leads to myriad changes in processing in the central auditory system. We recently described task-related plasticity characterized by rapid modulation of spectro-temporal receptive fields (STRFs) in ferret primary auditory cortex (A1) during tone detection. We conjectured that each acoustic task may have its own "signature" STRF changes, dependent on the salient cues that the animal must attend to perform the task. To discover whether other acoustic tasks could elicit changes in STRF shape, we recorded from A1 in ferrets also trained on a frequency discrimination task. Overall, we found a distinct pattern of STRF change, characterized by an expected selective enhancement at target tone frequency but also by an equally selective depression at reference tone frequency. When single-tone detection and frequency discrimination tasks were performed sequentially, neurons responded differentially to identical tones, reflecting distinct predictive values of stimuli in the two behavioral contexts. All results were observed in multiunit as well as single-unit recordings. Our findings provide additional evidence for the presence of adaptive neuronal responses in A1 that can swiftly change to reflect both sensory content and the changing behavioral meaning of incoming acoustic stimuli.

Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks.

The clinical efficacy of lithium in the prophylaxis of recurrent affective episodes in bipolar disorder is characterized by a lag in onset and remains for weeks to months after discontinuation. Thus, the long-term therapeutic effect of lithium likely requires reprogramming of gene expression. Protein kinase C and glycogen synthase kinase-3 signal transduction pathways are perturbed by chronic lithium at therapeutically relevant concentrations and have been implicated in modulating synaptic function in nerve terminals. These signaling pathways offer an opportunity to model critical signals for altering gene expression programs that underlie adaptive responses of neurons to long-term lithium exposure. While the precise physiological events critical for the clinical efficacy of lithium remain unknown, we propose that linking lithium-responsive genes as a regulatory network will provide a strategy to identify signature gene expression patterns that distinguish between therapeutic and nontherapeutic actions of lithium.

NF-κB p50 Is Increased in Neurons Surviving Hippocampal Injury

Signal transduction pathways that lead to the modulation of genes related to survival and repair mechanisms are activated in neurons that survive injury. These protein kinase/phosphatase cascades converge on transcription factors, the DNA binding proteins that directly regulate gene expression. In this study we examined expression of the NF-κB p50 subunit in the rat hippocampus 7 days after injury caused by middle cerebral artery occlusion or trimethyltin treatment. We found increased levels of p50 in neurons throughout the hippocampus after both treatments, localized not only in cell bodies but also in processes. At the 7-day time point, Fluoro-Jade histochemistry revealed hippocampal neurodegeneration in trimethyltin-treated rats but not in those lesioned by middle cerebral artery occlusion. p50 was not expressed in Fluoro-Jade-positive degenerating cells, supporting the role of this transcriptional subunit in neurosurvival. Because phosphorylation of the inhibitor IκB protein by IκB kinase is the classic step in NF-κB activation, phospho-IκBα immunoreactivity was examined as an indication of IκB kinase activity. Levels of phospho-IκBα were increased in neurons throughout the hippocampus 7 days postinjury. Immunoblotting for phospho-IκBα demonstrated increased levels 1 day postinjury that remained elevated for at least 7 days. These data suggest that NF-κB signal transduction is involved in an adaptive response of neurons that survive injury.

Expression of splice variants of the NR1 subunit of the N‐methyl‐d‐aspartate receptor in the normal and injured rat spinal cord

Quantitative western blot analysis in laminectomy control spinal cords of adult rats was used to provide the first report of the normal expression patterns of the N1, C1, C2 and C2' cassettes in the cervical, thoracic and lumbar regions of the spinal cord as a percent of total NR1 subunit protein. In all regions studied, the C1 and C2 cassettes were usually contained in less than 10% of total NR1 protein. In contrast, approximately 90% of total NR1 protein contained the C2' cassette. A significant proportion of total NR1 protein (approximately 30%) also contained the N1 cassette. These data are consistent with expression of NR1(000) (NR1-4a) and NR1(100) (NR1-4b) as the dominant splice forms in the spinal cord. Splice variant expression was also studied following incomplete, contusive spinal cord injury (SCI) to the thoracic level 8 (T8) region. This injury did not change expression of the C1 or C2 cassette in any region of the spinal cord acutely at 24 h or chronically at 1 month. There was an increase in expression of the N1 cassette in the lumbar regions 1 month after injury (p < 0.05). These data indicate that SCI induces distal changes in NR1 splice variant expression, which may play a role in the adaptive response of neurons in the chronically injured spinal cord.

Differential Regulation of Mitogen-Activated Protein Kinases ERK1/2 and ERK5 by Neurotrophins, Neuronal Activity, and cAMP in Neurons

Activation of the extracellular signal-regulated kinase 1 (ERK1) and ERK2 by neurotrophins, neuronal activity, or cAMP has been strongly implicated in differentiation, survival, and adaptive responses of neurons during development and in the adult brain. Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5, was discovered. Like ERK1 and ERK2, ERK5 is expressed in neurons, and ERK5 stimulation by epidermal growth factor is blocked by the MAP kinase/ERK kinase 1 (MEK1) inhibitors PD98059 and U0126. This suggests the interesting possibility that some of the functions attributed to ERK1/2 may be mediated by ERK5. However, the regulatory properties of ERK5 in primary cultured neurons have not been reported. Here we examined the regulation of ERK5 signaling in primary cultured cortical neurons. Our data demonstrate that, similar to ERK1/2, ERK5 is activated by neurotrophins including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4. BDNF stimulation of ERK5 required the activity of MEK5. Surprisingly, ERK5 was not stimulated by cAMP or neuronal activity induced by glutamate or membrane depolarization. In contrast to ERK1/2, ERK5 strongly activated the transcriptional activity of myocyte enhancer factor 2C (MEF2C) in pheochromocytoma 12 (PC12) cells and was required for neurotrophin stimulation of MEF2C transcription in both PC12 cells and cortical neurons. Furthermore, ERK1/2, but not ERK5, induced transcription from Elk1 and the cAMP/ Ca(2+) response element in PC12 cells. Our data suggest that mechanisms for regulation of ERK5 and downstream transcriptional pathways regulated by ERK5 are distinct from those of ERK1/2 in neurons. Furthermore, ERK5 is the first MAP kinase identified whose activity is stimulated by neurotrophins but not by neuronal activity.

The labile brain. II. Transients, complexity and selection.

The successive expression of neuronal transients is related to dynamic correlations and, as shown in this paper, to dynamic instability. Dynamic instability is a form of complexity, typical of neuronal systems, which may be crucial for adaptive brain function from two perspectives. The first is from the point of view of neuronal selection and self-organizing systems: if selective mechanisms underpin the emergence of adaptive neuronal responses then dynamic instability is, itself, necessarily adaptive. This is because dynamic instability is the source of diversity on which selection acts and is therefore subject to selective pressure. In short, the emergence of order, through selection, depends almost paradoxically on the instabilities that characterize the diversity of brain dynamics. The second perspective is provided by information theory.

Ca2+ Influx Regulates BDNF Transcription by a CREB Family Transcription Factor-Dependent Mechanism

CREB is a transcription factor implicated in the control of adaptive neuronal responses. Although one function of CREB in neurons is believed to be the regulation of genes whose products control synaptic function, the targets of CREB that mediate synaptic function have not yet been identified. This report describes experiments demonstrating that CREB or a closely related protein mediates Ca2+-dependent regulation of BDNF, a neurotrophin that modulates synaptic activity. In cortical neurons, Ca2+ influx triggers phosphorylation of CREB, which by binding to a critical Ca2+ response element (CRE) within the BDNF gene activates BDNF transcription. Mutation of the BDNF CRE or an adjacent novel regulatory element as well as a blockade of CREB function resulted in a dramatic loss of BDNF transcription. These findings suggest that a CREB family member acts cooperatively with an additional transcription factor(s) to regulate BDNF transcription. We conclude that the BDNF gene is a CREB family target whose protein product functions at synapses to control adaptive neuronal responses.

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.

A Defect in Nurturing in Mice Lacking the Immediate Early Gene fosB

Although expression of the Fos family of transcription factors is induced by environmental stimuli that trigger adaptive neuronal responses, eidence that Fos family members mediate these responses is lacking. To address this issue, mice were generated with an inactivating mutation in the fosB gene. fosB mutant mice are profoundly deficient in their ability to nurture young animals but are normal with respect to other cognitive and sensory functions. The nurturing defect is likely due to the absence of FosB in the preoptic area, a region of the hypothalamus that is critical for nurturing. These observations suggest that a transcription factor controls a complex behavior by regulating a specific neuronal circuit and indicate that nurturing in mammals has a genetic component.

Repetitive firing properties of putative dopamine-containing neurons in vitro: regulation by an apamin-sensitive Ca2+-activated K+ conductance

Intracellular recording techniques were used to study the effects of apamin (APA), a selective inhibitor of one type of Ca(2+)-activated K+ channel, on the electroresponsive properties of dopamine (DA)-containing neurons within the zona compacta of the substantia nigra (SNc) in rat. Bath application of APA (1 microM) blocked the slow component of a complex post-spike afterhyperpolarization (AHPs) without affecting other characteristics of the action potential. Blockade of AHPs was accompanied by an increase in the number and frequency of action potentials evoked by depolarizing current pulses. However, APA failed to affect the cellular mechanisms underlying spike frequency adaptation or post-stimulus inhibitory period. These data indicate that AHPs can exert a strong influence on the interspike interval but is probably not involved in regulating slower adaptive neuronal responses.

Evidence for the involvement of protein kinase C in neurodegenerative changes in cultured human cortical neurons

Roles of protein kinases in mediating adaptive neuronal responses to activation of signal transduction pathways are well known. Recent findings suggest that kinases may also be involved in pathological processes in the nervous system. The present study employed cultured human cerebral cortical neurons to test the hypothesis that overactivation of protein kinase C (PKC) can result in neurodegeneration. Phorbol 12-myristate 13-acetate (PMA), an activator of PKC, caused the degeneration of neurons over a period of 3–24 h. The PKC inhibitor H-7 prevented the neurodegeneration normally caused by PMA, and an inactive phorbol (4α-phorbol 12,13-didecanoate; PDD) did not cause neurodegeneration. The neurodegeneration caused by PMA was independent of calcium influx. Immunoreactivity toward antibodies that recognize the microtubule-associated protein tau in Alzheimer neurofibrillary tangles (Alz-50 and 5E2) was greatly increased in neurons exposed to PMA. The antigenic changes were prevented by H-7. These findings indicate that high levels of activation of PKC can cause neurodegeneration and are consistent with the possibility that altered cellular signaling contributes to pathological neuronal degeneration in the intact nervous system.