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J Neurosci [journal]
- Inhibition of Adenylyl Cyclase Type 5 Prevents l-DOPA-Induced Dyskinesia in an Animal Model of Parkinson's Disease. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11744-53.
The dopamine precursor l-3,4-dihydroxyphenylalanine (l-DOPA) is widely used as a therapeutic choice for the treatment of patients with Parkinson's disease. However, the long-term use of l-DOPA leads to the development of debilitating involuntary movements, called l-DOPA-induced dyskinesia (LID). The cAMP/protein kinase A (PKA) signaling in the striatum is known to play a role in LID. However, from among the nine known adenylyl cyclases (ACs) present in the striatum, the AC that mediates LID remains unknown. To address this issue, we prepared an animal model with unilateral 6-hydroxydopamine lesions in the substantia nigra in wild-type and AC5-knock-out (KO) mice, and examined behavioral responses to short-term or long-term treatment with l-DOPA. Compared with the behavioral responses of wild-type mice, LID was profoundly reduced in AC5-KO mice. The behavioral protection of long-term treatment with l-DOPA in AC5-KO mice was preceded by a decrease in the phosphorylation levels of PKA substrates ERK (extracellular signal-regulated kinase) 1/2, MSK1 (mitogen- and stress-activated protein kinase 1), and histone H3, levels of which were all increased in the lesioned striatum of wild-type mice. Consistently, FosB/ΔFosB expression, which was induced by long-term l-DOPA treatment in the lesioned striatum, was also decreased in AC5-KO mice. Moreover, suppression of AC5 in the dorsal striatum with lentivirus-shRNA-AC5 was sufficient to attenuate LID, suggesting that the AC5-regulated signaling cascade in the striatum mediates LID. These results identify the AC5/cAMP system in the dorsal striatum as a therapeutic target for the treatment of LID in patients with Parkinson's disease.
- Unification of neuronal spikes, seizures, and spreading depression. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11733-43.
The pathological phenomena of seizures and spreading depression have long been considered separate physiological events in the brain. By incorporating conservation of particles and charge, and accounting for the energy required to restore ionic gradients, we extend the classic Hodgkin-Huxley formalism to uncover a unification of neuronal membrane dynamics. By examining the dynamics as a function of potassium and oxygen, we now account for a wide range of neuronal activities, from spikes to seizures, spreading depression (whether high potassium or hypoxia induced), mixed seizure and spreading depression states, and the terminal anoxic "wave of death." Such a unified framework demonstrates that all of these dynamics lie along a continuum of the repertoire of the neuron membrane. Our results demonstrate that unified frameworks for neuronal dynamics are feasible, can be achieved using existing biological structures and universal physical conservation principles, and may be of substantial importance in enabling our understanding of brain activity and in the control of pathological states.
- Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11723-32.
Loss-of-function mutations in the α3 isoform of the Na(+)/K(+) ATPase (sodium pump) are responsible for rapid-onset dystonia parkinsonism (DYT12). Recently, a pharmacological model of DYT12 was generated implicating both the cerebellum and basal ganglia in the disorder. Notably, partially blocking sodium pumps in the cerebellum was necessary and sufficient for induction of dystonia. Thus, a key question that remains is how partially blocking sodium pumps in the cerebellum induces dystonia. In vivo recordings from dystonic mice revealed abnormal high-frequency bursting activity in neurons of the deep cerebellar nuclei (DCN), which comprise the bulk of cerebellar output. In the same mice, Purkinje cells, which provide strong inhibitory drive to DCN cells, also fired in a similarly erratic manner. In vitro studies demonstrated that Purkinje cells are highly sensitive to sodium pump dysfunction that alters the intrinsic pacemaking of these neurons, resulting in erratic burst firing similar to that identified in vivo. This abnormal firing abates when sodium pump function is restored and dystonia caused by partial block of sodium pumps can be similarly alleviated. These findings suggest that persistent high-frequency burst firing of cerebellar neurons caused by sodium pump dysfunction underlies dystonia in this model of DYT12.
- A model of the medial superior olive explains spatiotemporal features of local field potentials. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11705-22.
Local field potentials are important indicators of in vivo neural activity. Sustained, phase-locked, sound-evoked extracellular fields in the mammalian auditory brainstem, known as the auditory neurophonic, reflect the activity of neurons in the medial superior olive (MSO). We develop a biophysically based model of the neurophonic that accounts for features of in vivo extracellular recordings in the cat auditory brainstem. By making plausible idealizations regarding the spatial symmetry of MSO neurons and the temporal synchrony of their afferent inputs, we reduce the challenging problem of computing extracellular potentials in a 3D volume conductor to a one-dimensional problem. We find that postsynaptic currents in bipolar MSO neuron models generate extracellular voltage responses that strikingly resemble in vivo recordings. Simulations reproduce distinctive spatiotemporal features of the in vivo neurophonic response to monaural pure tones: large oscillations (hundreds of microvolts to millivolts), broad spatial reach (millimeter scale), and a dipole-like spatial profile. We also explain how somatic inhibition and the relative timing of bilateral excitation may shape the spatial profile of the neurophonic. We observe in simulations, and find supporting evidence in in vivo data, that coincident excitatory inputs on both dendrites lead to a drastically reduced spatial reach of the neurophonic. This outcome surprises because coincident inputs are thought to evoke maximal firing rates in MSO neurons, and it reconciles previously puzzling evoked potential results in humans and animals. The success of our model, which has no axon or spike-generating sodium currents, suggests that MSO spikes do not contribute appreciably to the neurophonic.
- Engrailed alters the specificity of synaptic connections of Drosophila auditory neurons with the giant fiber. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11691-704.
We show that a subset of sound-detecting Johnston's Organ neurons (JONs) in Drosophila melanogaster, which express the transcription factors Engrailed (En) and Invected (Inv), form mixed electrical and chemical synaptic inputs onto the giant fiber (GF) dendrite. These synaptic connections are detected by trans-synaptic Neurobiotin (NB) transfer and by colocalization of Bruchpilot-short puncta. We then show that misexpressing En postmitotically in a second subset of sound-responsive JONs causes them to form ectopic electrical and chemical synapses with the GF, in turn causing that postsynaptic neuron to redistribute its dendritic branches into the vicinity of these afferents. We also introduce a simple electrophysiological recording paradigm for quantifying the presynaptic and postsynaptic electrical activity at this synapse, by measuring the extracellular sound-evoked potentials (SEPs) from the antennal nerve while monitoring the likelihood of the GF firing an action potential in response to simultaneous subthreshold sound and voltage stimuli. Ectopic presynaptic expression of En strengthens the synaptic connection, consistent with there being more synaptic contacts formed. Finally, RNAi-mediated knockdown of En and Inv in postmitotic neurons reduces SEP amplitude but also reduces synaptic strength at the JON-GF synapse. Overall, these results suggest that En and Inv in JONs regulate both neuronal excitability and synaptic connectivity.
- Deletion of prostaglandin e2 synthesizing enzymes in brain endothelial cells attenuates inflammatory Fever. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11684-90.
Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE2 remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammation-induced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE2 synthesis in brain endothelial cells is critical for inflammation-induced fever.
- Molecular Mechanisms Contributing to TARP Regulation of Channel Conductance and Polyamine Block of Calcium-Permeable AMPA Receptors. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11673-83.
Many properties of fast synaptic transmission in the brain are influenced by transmembrane AMPAR regulatory proteins (TARPs) that modulate the pharmacology and gating of AMPA-type glutamate receptors (AMPARs). Although much is known about TARP influence on AMPAR pharmacology and kinetics through their modulation of the extracellular ligand-binding domain (LBD), less is known about their regulation of the ion channel region. TARP-induced modifications in AMPAR channel behavior include increased single-channel conductance and weakened block of calcium-permeable AMPARs (CP-AMPARs) by endogenous intracellular polyamines. To investigate how TARPs modify ion flux and channel block, we examined the action of γ-2 (stargazin) on GluA1 and GluA4 CP-AMPARs. First, we compared the permeation of organic cations of different sizes. We found that γ-2 increased the permeability of several cations but not the estimated AMPAR pore size, suggesting that TARP-induced relief of polyamine block does not reflect altered pore diameter. Second, to determine whether residues in the TARP intracellular C-tail regulate polyamine block and channel conductance, we examined various γ-2 C-tail mutants. We identified the membrane proximal region of the C terminus as crucial for full TARP-attenuation of polyamine block, whereas complete deletion of the C-tail markedly enhanced the TARP-induced increase in channel conductance; thus, the TARP C-tail influences ion permeation. Third, we identified a site in the pore-lining region of the AMPAR, close to its Q/R site, that is crucial in determining the TARP-induced changes in single-channel conductance. This conserved residue represents a site of TARP action, independent of the AMPAR LBD.
- Fine-scale plasticity of microscopic saccades. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11665-72.
When asked to maintain their gaze steady on a given location, humans continually perform microscopic eye movements, including fast gaze shifts known as microsaccades. It has long been speculated that these movements may contribute to the maintenance of fixation, but evidence has remained contradictory. We used a miniaturized version of saccadic adaptation, an experimental procedure by which motor control of saccades is modified through intrasaccadic displacements of the target. We found that the statistical distribution of microsaccade amplitudes changes after brief exposure to systematic shifts of the fixation point during microsaccade occurrence. Shifts in the same directions as microsaccades produce movements with larger amplitudes, whereas shifts against microsaccade directions result in smaller movements. Our findings show that microsaccades are precisely monitored during fixation and that their motor program is modified if the postsaccadic target position is not at the expected retinal location. These results demonstrate that saccadic adaptation occurs even when the stimulus is already close to the foveal center and precise execution of the movement may not be critical. They support the proposal that adaptation is necessary to maintain a consistent relationship between motor control and its visual consequences and that the representation of space is intrinsically multimodal, even during fixation.
- Beyond blindsight: properties of visual relearning in cortically blind fields. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11652-64.
Damage to the primary visual cortex (V1) or its immediate afferents results in a dense scotoma, termed cortical blindness (CB). CB subjects have residual visual abilities, or blindsight, which allow them to detect and sometimes discriminate stimuli with high temporal and low spatial frequency content. Recent work showed that with training, discriminations in the blind field can become more reliable, and even reach consciousness. However, the narrow spatiotemporal bandwidth of blindsight limits its functional usefulness in everyday vision. Here, we asked whether visual training can induce recovery outside the spatiotemporal bandwidth of blindsight. Specifically, could human CB subjects learn to discriminate static, nonflickering stimuli? Can such learning transfer to untrained stimuli and tasks, and does double training with moving and static stimuli provide additional advantages relative to static training alone? We found CB subjects capable of relearning static orientation discriminations following single as well as double training. However, double training with complex, moving stimuli in a separate location was necessary to recover complex motion thresholds at locations trained with static stimuli. Subjects trained on static stimuli alone could only discriminate simple motion. Finally, both groups had approximately equivalent, incomplete recovery of fine orientation and direction discrimination thresholds, as well as contrast sensitivity. These results support two conclusions: (1) from a practical perspective, complex moving stimuli and double training may be superior training tools for inducing visual recovery in CB, and (2) the cortically blind visual system can relearn to perform a wider range of visual discriminations than predicted by blindsight alone.
- Synaptopodin regulates spine plasticity: mediation by calcium stores. [Journal Article]
- J Neurosci 2014 Aug 27; 34(35):11641-51.
The role of synaptopodin (SP), an actin-binding protein residing in dendritic spines, in synaptic plasticity was studied in dissociated cultures of hippocampus taken from control and SP knock-out (SPKO) mice. Unlike controls, SPKO cultures were unable to express changes in network activity or morphological plasticity after intense activation of their NMDA receptors. SPKO neurons were transfected with SP-GFP, such that the only SP resident in these neurons is the fluorescent species. The localization and intensity of the transfected SP were similar to that of the native one. Because less than half of the spines in the transfected neurons contained SP, comparisons were made between SP-containing (SP(+)) and SP lacking (SP(-)) spines in the same dendritic segments. Synaptic plasticity was induced either in the entire network by facilitation of the activation of the NMDA receptor, or specifically by local flash photolysis of caged glutamate. After activation, spines that were endowed with SP puncta were much more likely to expand than SP(-) spines. The spine expansion was suppressed by thapsigargin, which disables calcium stores. The mechanism through which SP may promote plasticity is indicated by the observations that STIM-1, the sensor of calcium concentration in stores, and Orai-1, the calcium-induced calcium entry channel, are colocalized with SP, in the same dendritic spines. The structural basis of SP is likely to be the spine apparatus, found in control but not in SPKO cells. These results indicate that SP has an essential, calcium store-related role in regulating synaptic plasticity in cultured hippocampal neurons.