Cellular and Molecular Neurobiology: The Brain and Cognitive Sciences III >> Content Detail

Study Materials


The readings listed below are the foundation of this course. Where available, journal article abstracts from PubMed (an online database providing access to citations from biomedical literature) are included.

Student Presentations

Students choose from the following topics, and read the articles listed for that topic, in preparation for their class presentations.

Potassium Channels

Choe. "Potassium Channel Structures," Nat Rev Neurosci. 2002 Feb;3(2):115 [background and review].

PubMed abstract:  The molecular basis of K+ channel function is universally conserved. K+ channels allow K+ flux and are essential for the generation of electric current across excitable membranes. K+ channels are also the targets of various intracellular control mechanisms, such that the suboptimal regulation of channel function might be related to pathological conditions. Because of the fundamental role of K+ channels in controlling membrane excitability, a structural understanding of their function and regulation will provide a useful framework for understanding neuronal physiology. Many recent physiological and crystallographic studies have led to new insights into the workings of K+ channels.

Doyle, et al. "The Structure of the Potassium Channel: Molecular Basis of K+ Conduction and Selectivity," Science. 1998 Apr 3;280(5360):69-77 [primary article].

PubMed abstract:  The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K+ channels, particularly in the pore region. X-ray analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K+ channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K+ ions but not smaller Na+ ions. The selectivity filter contains two K+ ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K+ ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K+ conduction.

He, et al. "Regulation of Opioid Receptor Trafficking and Morphine Tolerance by Receptor Oligomerization," Cell. 2002 Jan 25;108(2):271-82 [primary article].

PubMed abstract:  The utility of morphine for the treatment of chronic pain is hindered by the development of tolerance to the analgesic effects of the drug. Morphine is unique among opiates in its ability to activate the mu opioid receptor (MOR) without promoting its desensitization and endocytosis. Here we demonstrate that [D-Ala(2)-MePhe(4)-Gly(5)-ol] enkephalin (DAMGO) can facilitate the ability of morphine to stimulate MOR endocytosis. As a consequence, rats treated chronically with both drugs show reduced analgesic tolerance compared to rats treated with morphine alone. These results demonstrate that endocytosis of the MOR can reduce the development of tolerance, and hence suggest an approach for the development of opiate analogs with enhanced efficacy for the treatment of chronic pain.

Pierce, et al. "Seven-Transmembrane Receptors," Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50 [background and review].

PubMed abstract:  Seven-transmembrane receptors, which constitute the largest, most ubiquitous and most versatile family of membrane receptors, are also the most common target of therapeutic drugs. Recent findings indicate that the classical models of G-protein coupling and activation of second-messenger-generating enzymes do not fully explain their remarkably diverse biological actions.

Neural Induction

Piccolo, et al. "Dorsoventral Patterning in Xenopus: Inhibition of Ventral Signals by Direct Binding of Chordin to BMP-4." Cell. 1996 Aug 23;86(4):589-98.

PubMed abstract:  Chordin (Chd) is an abundant protein secreted by Spemann organizer tissue during gastrulation. Chd antagonizes signaling by mature bone morphogenetic proteins (BMPs) by blocking binding to their receptors. Recombinant Xenopus Chd binds to BMP-4 with high affinity (KD, 3 x 10(-10) M), binding specifically to BMPs but not to activin or TGF-beta1. Chd protein is able to dorsalize mesoderm and to neuralize ectoderm in Xenopus gastrula explants at 1 nM. We propose that the noncell-autonomous effects of Spemann's organizer on dorsoventral patterning are executed in part by diffusible signals that directly bind to and neutralize ventral BMPs during gastrulation.


Houart, et al. "Establishment of the Telencephalon during Gastrulation by Local Antagonism of Wnt Signaling." Neuron. 2002 Jul 18;35(2):255-65.

PubMed abstract:  Cells at the anterior boundary of the neural plate (ANB) can induce telencephalic gene expression when transplanted to more posterior regions. Here, we identify a secreted Frizzled-related Wnt antagonist, Tlc, that is expressed in ANB cells and can cell nonautonomously promote telencephalic gene expression in a concentration-dependent manner. Moreover, abrogation of Tlc function compromises telencephalic development. We also identify Wnt8b as a locally acting modulator of regional fate in the anterior neural plate and a likely target for antagonism by Tlc. Finally, we show that tlc expression is regulated by signals that establish early antero-posterior and dorso-ventral ectodermal pattern. From these studies, we propose that local antagonism of Wnt activity within the anterior ectoderm is required to establish the telencephalon.

Neurogenesis and Migration

Wu, et al. "Directional guidance of neuronal migration in the olfactory system by the protein Slit." Nature. 1999 Jul 22;400(6742):331-6.

PubMed abstract:  Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration have remained unclear. Here we report that the secreted protein Slit repels neuronal precursors migrating from the anterior subventricular zone in the telencephalon to the olfactory bulb. Our results provide a direct demonstration of a molecular cue whose concentration gradient guides the direction of migrating neurons. They also support a common guidance mechanism for axon projection and neuronal migration and suggest that Slit may provide a molecular tool with potential therapeutic applications in controlling and directing cell migration.

Neuronal Cell Biology, Subcellular Specialization

Hering and Sheng. "Dendritic spines: structure, dynamics and regulation." Nat Rev Neurosci. 2001 Dec;2(12):880-8. [Background and Review].

Shi, et al. "Hippocampal Neuronal Polarity Specified by Spatially Localized mPar3/mPar6 and PI 3-Kinase Activity." Cell. 2003 Jan 10;112(1):63-75. [Primary Article].

PubMed abstract:  How a neuron becomes polarized remains an outstanding question. Here, we report that selection of the future axon among neurites of a cultured hippocampal neuron requires the activity of growth factor receptor tyrosine kinase, phosphatidylinositol 3-kinase (PI 3-kinase), as well as atypical protein kinase C (aPKC). The PI 3-kinase activity, highly localized to the tip of the newly specified axon of stage 3 neurons, is essential for the proper subcellular localization of mPar3, the mammalian homolog of C. elegans polarity protein Par3. Polarized distribution of not only mPar3 but also mPar6 is important for axon formation; ectopic expression of mPar6 or mPar3, or just the N terminus of mPar3, leaves neurons with no axon specified. Thus, neuronal polarity is likely to be controlled by the mPar3/mPar6/aPKC complex and the PI 3-kinase signaling pathway, both serving evolutionarily conserved roles in specifying cell polarity.

Protein Targeting, Signaling Complexes

Sheng and Sala. "PDZ domains and the organization of supramolecular complexes." Annu Rev Neurosci. 2001;24:1-29. [Background and Review].

PubMed abstract:  PDZ domains are modular protein interaction domains that bind in a sequence-specific fashion to short C-terminal peptides or internal peptides that fold in a beta-finger. The diversity of PDZ binding specificities can be explained by variable amino acids lining the peptide-binding groove of the PDZ domain. Abundantly represented in Caenorhabditis elegans, Drosophila melanogaster, and mammalian genomes, PDZ domains are frequently found in multiple copies or are associated with other protein-binding motifs in multidomain scaffold proteins. PDZ-containing proteins are typically involved in the assembly of supramolecular complexes that perform localized signaling functions at particular subcellular locations. Organization around a PDZ-based scaffold allows the stable localization of interacting proteins and enhances the rate and fidelity of signal transduction within the complex. Some PDZ-containing proteins are more dynamically regulated in distribution and may also be involved in the trafficking of interacting proteins within the cell.

Tsunoda, et al. "A multivalent PDZ-domain protein assembles signalling complexes in a G-protein-coupled cascade." Nature. 1997 Jul 17;388(6639):243-9.[Primary Article].

PubMed abstract:  How are signalling molecules organized into different pathways within the same cell? In Drosophila, the inaD gene encodes a protein consisting of five PDZ domains which serves as a scaffold to assemble different components of the phototransduction cascade, including the principal light-activated ion channels, the effector phospholipase C-beta and protein kinase C. Null inaD mutants have a dramatically reorganized subcellular distribution of signalling molecules, and a total loss of transduction complexes. Also, mutants defective in a single PDZ domain produce signalling complexes that lack the target protein and display corresponding defects in their physiology. A picture emerges of a highly organized unit of signalling, a 'transduclisome', with PDZ domains functioning as key elements in the organization of transduction complexes in vivo.

Neuronal Determination and Differentiation

Wichterle, et al. "Directed Differentiation of Embryonic Stem Cells into Motor Neurons." Cell. 2002 Aug 9;110(3):385-97.

PubMed abstract:  Inductive signals and transcription factors involved in motor neuron generation have been identified, raising the question of whether these developmental insights can be used to direct stem cells to a motor neuron fate. We show that developmentally relevant signaling factors can induce mouse embryonic stem (ES) cells to differentiate into spinal progenitor cells, and subsequently into motor neurons, through a pathway recapitulating that used in vivo. ES cell-derived motor neurons can populate the embryonic spinal cord, extend axons, and form synapses with target muscles. Thus, inductive signals involved in normal pathways of neurogenesis can direct ES cells to form specific classes of CNS neurons.

Axon Guidance I: Growth Cone Motility; Cues and Receptors

Stein and Tessier-Lavigne. "Hierarchical Organization of Guidance Receptors: Silencing of Netrin Attraction by Slit Through a Robo/DCC Receptor Complex." Science. 2001 Mar 9;291(5510):1928-38. Epub 2001 Feb 08.

PubMed abstract:  Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: They become repelled by the repellent Slit and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Here, we provide evidence that these two changes are causally linked: In the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation.

Axon Guidance II: Cytoplasmic Signaling Pathways; Axon Target Recognition

Schmucker, et al. "Drosophila Dscam Is an Axon Guidance Receptor Exhibiting Extraordinary Molecular Diversity." Cell. 2000 Jun 9;101(6):671-84.

PubMed abstract:  A Drosophila homolog of human Down syndrome cell adhesion molecule (DSCAM), an immunoglobulin superfamily member, was isolated by its affinity to Dock, an SH3/SH2 adaptor protein required for axon guidance. Dscam binds directly to both Dock's SH2 and SH3 domains. Genetic studies revealed that Dscam, Dock and Pak, a serine/threonine kinase, act together to direct pathfinding of Bolwig's nerve, containing a subclass of sensory axons, to an intermediate target in the embryo. Dscam also is required for the formation of axon pathways in the embryonic central nervous system. cDNA and genomic analyses reveal the existence of multiple forms of Dscam with a conserved architecture containing variable Ig and transmembrane domains. Alternative splicing can potentially generate more than 38,000 Dscam isoforms. This molecular diversity may contribute to the specificity of neuronal connectivity.

Cell Death and Survival I: Neurotrophic Hypothesis, Survival Factors/Receptors

Kuruvilla, et al. "Spatially and Functionally Distinct Roles of the PI3-K Effector Pathway during NGF Signaling in Sympathetic Neurons." Neuron. 2000 Sep;27(3):499-512.

PubMed abstract:  NGF is a target-derived growth factor for developing sympathetic neurons. Here, we show that application of NGF exclusively to distal axons of sympathetic neurons leads to an increase in PI3-K signaling in both distal axons and cell bodies. In addition, there is a more critical dependence on PI3-K for survival of neurons supported by NGF acting exclusively on distal axons as compared to neurons supported by NGF acting directly on cell bodies. Interestingly, PI3-K signaling within both cell bodies and distal axons contributes to survival of neurons. The requirement for PI3-K signaling in distal axons for survival may be explained by the finding that inhibition of PI3-K in the distal axons attenuates retrograde signaling. Therefore, a single TrkA effector, PI3-K, has multiple roles within spatially distinct cellular locales during retrograde NGF signaling.

Cell Death and Survival II: Cell Death Pathways, Developmental Uses & Pathological Aspects

Nakatomi, et al. "Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors." Cell. 2002 Aug 23;110(4):429-41.

PubMed abstract:  The adult brain is extremely vulnerable to various insults. The recent discovery of neural progenitors in adult mammals, however, raises the possibility of repairing damaged tissue by recruiting their latent regenerative potential. Here we show that activation of endogenous progenitors leads to massive regeneration of hippocampal pyramidal neurons after ischemic brain injury. Endogenous progenitors proliferate in response to ischemia and subsequently migrate into the hippocampus to regenerate new neurons. Intraventricular infusion of growth factors markedly augments these responses, thereby increasing the number of newborn neurons. Our studies suggest that regenerated neurons are integrated into the existing brain circuitry and contribute to ameliorating neurological deficits. These results expand the possibility of novel neuronal cell regeneration therapies for stroke and other neurological diseases.

Synaptic Transmission I (Presynaptic Mechanisms)

Marek and Davis. "Transgenically Encoded Protein Photoinactivation (FlAsH-FALI): Acute Inactivation of Synaptotagmin I." Neuron. 2002 Dec 5;36(5):805-13.

PubMed abstract:  We demonstrate a noninvasive technique for protein photoinactivation using a transgenically encoded tag. A tetracysteine motif that binds the membrane-permeable fluorescein derivative 4',5'-bis(1,3,2-dithioarsolan-2-yl)fluorescein (FlAsH) was engineered into synaptotagmin I (Syt I4C). Neuronally expressed Syt I4C rescues the syt I null mutation, can be visualized after FlAsH labeling, and is normally distributed at the Drosophila neuromuscular synapse. Illumination of FlAsH bound Syt I4C at 488 nm decreases evoked release in seconds demonstrating efficient fluorophore-assisted light inactivation (FlAsH-FALI) of Syt I. The inactivation of Syt I is proportional to the duration of illumination and follows first-order kinetics. In addition, Syt I FlAsH-FALI is specific and does not impair Syt I-independent vesicle fusion. We demonstrate that Syt I is required for a post-docking step during vesicle fusion but does not function to stabilize the docked vesicle state.

Synaptic Transmission II (Postsynaptic Mechanisms)

Sheng and Lee. "AMPA Receptor Trafficking and the Control of Synaptic Transmission." Cell. 2001 Jun 29;105(7):825-8. [Background and Review].

Shi, et al. "Subunit-Specific Rules Governing AMPA Receptor Trafficking to Synapses in Hippocampal Pyramidal Neurons." Cell. 2001 May 4;105(3):331-43.[Primary Article].

PubMed abstract:  AMPA-type glutamate receptors (AMPA-Rs) mediate a majority of excitatory synaptic transmission in the brain. In hippocampus, most AMPA-Rs are hetero-oligomers composed of GluR1/GluR2 or GluR2/GluR3 subunits. Here we show that these AMPA-R forms display different synaptic delivery mechanisms. GluR1/GluR2 receptors are added to synapses during plasticity; this requires interactions between GluR1 and group I PDZ domain proteins. In contrast, GluR2/GluR3 receptors replace existing synaptic receptors continuously; this occurs only at synapses that already have AMPA-Rs and requires interactions by GluR2 with NSF and group II PDZ domain proteins. The combination of regulated addition and continuous replacement of synaptic receptors can stabilize long-term changes in synaptic efficacy and may serve as a general model for how surface receptor number is established and maintained.

Model Systems for Plasticity Studies: Pre- and Post-synaptic Mechanisms

Antonov, et al. "The contribution of facilitation of monostnaptic PSPs to dishabituation and sensitization of the Aplysia siphon withdrawal reflex." J Neurosci. 1999 Dec 1;19(23):10438-50. [Primary Article].

PubMed abstract:  To examine the relationship between synaptic plasticity and learning and memory as directly as possible, we have developed a new simplified preparation for studying the siphon-withdrawal reflex of Aplysia in which it is relatively easy to record synaptic connections between individual identified neurons during simple forms of learning. We estimated that monosynaptic EPSPs from LE siphon sensory neurons to LFS siphon motor neurons mediate approximately one-third of the reflex response measured in this preparation, which corresponds to siphon flaring in the intact animal. To investigate cellular mechanisms contributing to dishabituation and sensitization, we recorded evoked firing of LFS neurons, the siphon withdrawal produced by stimulation of an LFS neuron, the complex PSP in an LFS neuron, and the monosynaptic PSP from an "on-field" or "off-field" LE neuron to an LFS neuron during behavioral training. Unlike the simplified gill-withdrawal preparation (Cohen et al., 1997; Frost et al., 1997), in the siphon-withdrawal preparation we found no qualitative differences between the major cellular mechanisms contributing to dishabituation and sensitization, suggesting that dissociations that have been observed previously may be attributable to transient inhibition that does not occur for this component of the reflex. Furthermore, in the siphon-withdrawal preparation, all of the various cellular measures, including monosynaptic PSPs from either on-field or off-field LE neurons, changed approximately in parallel with changes in the behavior. These results provide the most direct evidence so far available that both dishabituation and sensitization involve multiple mechanisms, including heterosynaptic facilitation of sensory neuron-motor neuron PSPs.

Baeumont and Zucker. "Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels." Nat Neurosci. 2000 Feb;3(2):133-41.[Background Reading].

PubMed abstract:  Presynaptic activation of adenylyl cyclase and subsequent generation of cAMP represent an important mechanism in the modulation of synaptic transmission. In many cases, short- to medium-term modulation of synaptic strength by cAMP is due to activation of protein kinase A and subsequent covalent modification of presynaptic ion channels or synaptic proteins. Here we show that presynaptic cAMP generation via serotonin receptor activation directly modulated hyperpolarization-activated cation channels (Ih channels) in axons. This modulation of Ih produced an increase in synaptic strength that could not be explained solely by depolarization of the presynaptic membrane. These studies identify a mechanism by which cAMP and Ih regulate synaptic plasticity.

Regehr and Stevens. "Physiology of Synaptic Transmission and Short-Term Plasticity, Chap. 3 in Synaptic Physiology. [Important background reading] [From _Synapses_] Edited by Cowan, Sudhof, and Stevens, 2001, pp. 135-175.

Plasticity at the Neuromuscular Junction

Barber and Lichtman, "Activity-Driven Synapse Elimination Leads Paradoxically to Domination by Inactive Neurons." J Neurosci. 1999 Nov 15;19(22):9975-85. [Background Reading].

PubMed abstract:  In early postnatal life, multiple motor axons converge at individual neuromuscular junctions. However, during the first few weeks after birth, a competitive mechanism eliminates all the inputs but one. This phenomenon, known as synapse elimination, is thought to result from competition based on interaxonal differences in patterns or levels of activity (for review, see Lichtman,1995). Surprisingly, experimental data support two opposite views of the role of activity: that active axons have a competitive advantage (Ribchester and Taxt, 1983; Ridge and Betz, 1984; Balice-Gordon and Lichtman, 1994) and that inactive axons have a competitive advantage (Callaway et al., 1987, 1989). To understand this paradox, we have formulated a mathematical model of activity-mediated synapse elimination. We assume that the total amount of transmitter released, rather than the frequency of release, mediates synaptic competition. We further assume that the total synaptic area that a neuron can support is metabolically constrained by its activity level and size. This model resolves the paradox by showing that a competitive advantage of higher frequency axons early in development is overcome at later stages by greater synaptic efficacy of axons firing at a lower rate. This model both provides results consistent with experiments in which activity has been manipulated and an explanation for the origin of the size principle (Henneman, 1985).

Coleman, et al. "Alterations in Synaptic Strength Preceding Axon Withdrawal." [Primary Article], 1997.

Bird song: Plasticity at the Behavioral and Circuit Level

Boettiger and Doupe, "Developmentally Restricted Synaptic Plasticity in a Songbird Nucleus Required for Song Learning." Neuron. 2001 Sep 13;31(5):809-18.[Background Reading].

PubMed abstract:  We provide evidence here of long-term synaptic plasticity in a songbird forebrain area required for song learning, the lateral magnocellular nucleus of the anterior neostriatum (LMAN). Pairing postsynaptic bursts in LMAN principal neurons with stimulation of recurrent collateral synapses had two effects: spike timing- and NMDA receptor-dependent LTP of the recurrent synapses, and LTD of thalamic afferent synapses that were stimulated out of phase with the postsynaptic bursting. Both types of plasticity were restricted to the sensory critical period for song learning, consistent with a role for each in sensory learning. The properties of the observed plasticity are appropriate to establish recurrent circuitry within LMAN that reflects the spatiotemporal pattern of thalamic afferent activity evoked by tutor song. Such circuit organization could represent a tutor song memory suitable for reinforcing particular vocal sequences during sensorimotor learning.

Livingston, et al. "Slow NMDA-EPSCs at synapses critical for song development are not required for song learning in zebra finches." Nat Neurosci. 2000 May;3(5):482-8.[Primary Article].

PubMed abstract:  Birdsong, like human speech, is learned via auditory experience during a developmentally restricted sensitive period. Within projection neurons of two avian forebrain nuclei, NMDA receptor-mediated EPSCs (NMDA-EPSCs) become fast during song development, a transition posited to limit learning. To discover whether slow NMDA-EPSCs at these synapses are required for learning, we delayed song learning beyond its normal endpoint, post-hatch day (PHD) 65, by raising zebra finches in isolation from song tutors. At PHD45, before learning, isolation delayed NMDA-EPSC maturation, but only transiently. By PHD65, NMDA-EPSCs in isolates were fast and adult-like, yet isolates presented with tutors readily learned song. Thus song learning did not require slow NMDA-EPSCs at synapses critical for song development.

Multimodal Maps and Use-dependent Expansions of Sensitivity

Gutfreund, et al. "Gated Visual Input to the Central Auditory System." Science. 2002 Aug 30;297(5586):1556-9.[Background Reading].

PubMed abstract:  The central auditory system translates sound localization cues into a map of space guided, in part, by visual experience. In barn owls, this process takes place in the external nucleus of the inferior colliculus (ICX). However, to date, no trace of visual activity has been observed in this auditory nucleus. Here we show that strong visual responses, which are appropriate to guide auditory plasticity, appear in the ICX when inhibition is blocked in the optic tectum. Thus, visual spatial information is gated into the auditory system by an inhibitory mechanism that operates at a higher level in the brain.

Zheng and Knudsen, "Functional Selection of Adaptive Auditory Space Map by GABAA-Mediated Inhibition." Science. 1999 May 7;284(5416):962-5. [Primary Article].

PubMed abstract:  The external nucleus of the inferior colliculus in the barn owl contains an auditory map of space that is based on the tuning of neurons for interaural differences in the timing of sound. In juvenile owls, this region of the brain can acquire alternative maps of interaural time difference as a result of abnormal experience. It has been found that, in an external nucleus that is expressing a learned, abnormal map, the circuitry underlying the normal map still exists but is functionally inactivated by inhibition mediated by gamma-aminobutyric acid type A (GABAA) receptors. This inactivation results from disproportionately strong inhibition of specific input channels to the network. Thus, experience-driven changes in patterns of inhibition, as well as adjustments in patterns of excitation, can contribute critically to adaptive plasticity in the central nervous system.

Plasticity in Non-cortical Visual Areas

Sin, et al. "Dendrite growth increased by visual activity requires NMDA receptor and Rho GTPases." Nature. 2002 Oct 3;419(6906):475-80.[Primary Article].

PubMed abstract:  Previous studies suggest that neuronal activity may guide the development of synaptic connections in the central nervous system through mechanisms involving glutamate receptors and GTPase-dependent modulation of the actin cytoskeleton. Here we demonstrate by in vivo time-lapse imaging of optic tectal cells in Xenopus laevis tadpoles that enhanced visual activity driven by a light stimulus promotes dendritic arbor growth. The stimulus-induced dendritic arbor growth requires glutamate-receptor-mediated synaptic transmission, decreased RhoA activity and increased Rac and Cdc42 activity. The results delineate a role for Rho GTPases in the structural plasticity driven by visual stimulation in vivo.

Zhang, et al. "Visual input induces long-term potentiation of developing retinotectal synapses." Nat Neurosci. 2000 Jul;3(7):708-15. [Background Reading].

PubMed abstract:  Early visual experience is essential in the refinement of developing neural connections. In vivo whole-cell recording from the tectum of Xenopus tadpoles showed that repetitive dimming-light stimulation applied to the contralateral eye resulted in persistent enhancement of glutamatergic inputs, but not GABAergic or glycinergic inputs, on tectal neurons. This enhancement can be attributed to potentiation of retinotectal synapses. It required spiking of postsynaptic tectal cells as well as activation of NMDA receptors, and effectively occluded long-term potentiation (LTP) of retinotectal synapses induced by direct electrical stimulation of retinal ganglion cells. Thus, LTP-like synaptic modification can be induced by natural visual inputs and may be part of the underlying mechanism for the activity-dependent refinement of developing connections.

Visual Cortex Plasticity: History and Controversies

Hata, et al. "Selective Pruning of More Active Afferents When Cat Visual Cortex Is Pharmacologically Inhibited." Neuron. 1999 Feb;22(2):375-81. [Primary Article].

PubMed abstract:  Activity-dependent competition is thought to guide the normal development of specific patterns of neural connections. Such competition generally favors more active inputs, making them larger and stronger, while less active inputs become smaller and weaker. We pharmacologically inhibited the activity of visual cortical cells and measured the three-dimensional structure of inputs serving the two eyes when one eye was occluded. The more active inputs serving the open eye actually became smaller than the deprived inputs from the occluded eye, which were similar to those in normal animals. These findings demonstrate in vivo that it is not the amount of afferent activity but the correlation between cortical and afferent activity that regulates the growth or retraction of these inputs.

Rittenhouse, et al. "Monocular deprivation induces homosynaptic long-term depression in visual cortex." Nature. 1999 Jan 28;397(6717):347-50. [Background Reading].

PubMed abstract:  Brief monocular deprivation during early postnatal development can lead to a depression of synaptic transmission that renders visual cortical neurons unresponsive to subsequent visual stimulation through the deprived eye. The Bienenstock-Cooper-Munro (BCM) theory proposes that homosynaptic mechanisms of long-term depression (LTD) account for the deprivation effects. Homosynaptic depression, by definition, occurs only at active synapses. Thus, in contrast to the commonly held view that the synaptic depression caused by monocular deprivation is simply a result of retinal inactivity, this theoretical framework indicates that the synaptic depression may actually be driven by the residual activity in the visually deprived retina. Here we examine the validity of this idea by comparing the consequences of brief monocular deprivation by lid suture with those of monocular inactivation by intra-ocular treatment with tetrodotoxin. Lid suture leaves the retina spontaneously active, whereas tetrodotoxin eliminates all activity. In agreement with the BCM theory, our results show that monocular lid suture causes a significantly greater depression of deprived-eye responses in kitten visual cortex than does treatment with tetrodotoxin. These findings have important implications for mechanisms of experience-dependent plasticity in the neocortex.

Molecular Mechanisms of Cortical Plasticity

Hensch, et al. "Local GABA Circuit Control of Experience-Dependent Plasticity in Developing Visual Cortex." Science. 1998 Nov 20;282(5393):1504-8.[Primary Article].

PubMed abstract:  Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.

Kilman, et al. "Activity Deprivation Reduces Miniature IPSC Amplitude by Decreasing the Number of Postsynaptic GABAA Receptors Clustered at Neocortical Synapses." J Neurosci. 2002 Feb 15;22(4):1328-37.[Background Reading], 2002.

PubMed abstract:  Maintaining the proper balance between excitation and inhibition is necessary to prevent cortical circuits from either falling silent or generating epileptiform activity. One mechanism through which cortical networks maintain this balance is through the activity-dependent regulation of inhibition, but whether this is achieved primarily through changes in synapse number or synaptic strength is not clear. Previously, we found that 2 d of activity deprivation increased the amplitude of miniature EPSCs (mEPSCs) onto cultured visual cortical pyramidal neurons. Here we find that this same manipulation decreases the amplitude of mIPSCs. This occurs with no change in single-channel conductance but is accompanied by a reduction in the average number of channels open during the mIPSC peak and a reduction in the intensity of staining for GABA(A) receptors (GABA(A)Rs) at postsynaptic sites. In addition, the number of synaptic sites that express detectable levels of GABA(A)Rs was decreased by approximately 50% after activity blockade, although there was no reduction in the total number of presynaptic contacts. These data suggest that activity deprivation reduces cortical inhibition by reducing both the number of GABA(A)Rs clustered at synaptic sites and the number of functional inhibitory synapses. Because excitatory and inhibitory synaptic currents are regulated in opposite directions by activity blockade, these data suggest that the balance between excitation and inhibition is dynamically regulated by ongoing activity.

Plasticity and GABA Mediated Inhibition

Hardingham, et al. "Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways." Nat Neurosci. 2002 May;5(5):405-14.[Background Reading].

PubMed abstract:  Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. Specific blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss following stroke and other neuropathological conditions associated with glutamate toxicity.

Owens, et al. "Excitatory GABA Responses in Embryonic and Neonatal Cortical Slices Demonstrated by Gramicidin Perforated-Patch Recordings and Calcium Imaging." J Neurosci. 1996 Oct 15;16(20):6414-23.[Primary Article].

PubMed abstract:  Gramicidin perforated-patch-clamp recordings in brain slices were used to obtain an accurate assessment of the developmental change in the GABAA receptor reversal potential (EGABAA) in embryonic and early postnatal rat neocortical cells including neuroepithelial precursor cells, cortical plate neurons, and postnatal neocortical neurons. Our results demonstrate that there is a progressive negative shift in EGABAA with the most positive values found in the youngest cortical precursor cells. At the early stages of neocortical development, EGABAA is determined by the chloride (Cl-) gradient, and the internal chloride concentration ([Cl-]i) decreases with development. EGABAA is positive to the resting potential, indicating that GABA serves to depolarize developing neocortical cells. Consistent with this conclusion, GABAA receptor activation with muscimol was found-to increase the internal calcium concentration ([Ca2+]i) in both embryonic and early postnatal neocortical cells through the activation of voltage-gated calcium channels (VGCCs). Postnatal cells exhibit spontaneous postsynaptic synaptic currents, which are eliminated by bicuculline methiodide (BMI) but not glutamate receptor antagonists and reverse at the Cl- equilibrium potential. Likewise, brief spontaneous increases in [Ca2+]i, sensitive to BMI and TTX, are observed at the same ages, suggesting that endogenous synaptic GABAA receptor activation can depolarize cells and activate VGCCs. These results suggest that GABAA receptor-mediated depolarization may influence early neocortical developmental events, including neurogenesis and synaptogenesis, through the activation of Ca(2+)-dependent signal transduction pathways.



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