Activity-Dependent Development II April 25, 2007 Mu-ming Poo 1. The neurotrophin hypothesis 2. Maps in somatic sensory and motor cortices 3. Development of retinotopic map 4. Reorganization of cortical maps following sensory deprivation 5. Synaptic basis of cortical plasticity --- LTP and LTD 6. Relationship between developmental and adult plasticity The Neurotrophin Hypothesis Synaptic competition between co-innervating nerve terminals is determined by activity-dependent competition for the neurotrophin secreted by the postsynaptic cell. Criteria for neurotrophins to function as molecular signals in synaptic competition: 1) expressed in the right place and at the right time 2) secretion is activity-dependent 3) regulate synaptic functions 4) the amount and distribution are limited Neurotrophin hypothesis for activity-dependent competition from L eye from R eye pre- post- Development of ocular dominance (OD) columns in V1: - Axons from R eye relatively stronger, trigger the firing of postsynaptic cell - Postsynaptic depolarization triggers release of neurotrophins - Active presynaptic nerve terminals from R eyes take up the released neurotrophin, whereas the inactive (non-correlated) terminals inputs from the L eye do not receive the neurotrophin - Stabilization and growth of R eye inputs and regression and elimination of the L eye inputs 1
Molecular mechanism of cortical plasticity Evidence for the Neurotrophin Hypothesis: - infusion of BDNF (brain-derived neurotrophic factor) or NT-4/5, prevent formation of OD columns A Normal Layer 4 1.BDNF and NT-4 are expressed in the cortex 2. BDNF application potentiates excitatory synapses B NGF or NT-3 administration Layer 4 NGF NT-3 no effect C NT-4/5 or BDNF administration Layer 4 BDNF NT-4/5 Disrupt formation of OD column by Carla Shatz and co-workers Latest Findings: OD exists to some extent before eye opening Normal visual input may not be necessary for the initial formation, but required for fine tuning and maintenance of visual circuit Initial OD development may depend on spontaneous activity (e.g., retinal waves, correlated between neighboring RGC, but uncorrelated between the two eyes) Different colors represent activity of RGCs at different times sequentially (C. Shatz & R. Wong) CHAT-immunoreactive(IR) cells synthesize ACh Properties of Cortical Maps 1. Topographically ordered: Nearby points in periphery are represented by nearby cortical neurons. 2. Multiple Representations: The same set of sensory or motor information are represented repeatedly by multiple cortical areas. 3. Distorted mapping: Periphery points that required higher spatial resolution are represented with disproportional cortial areas (larger number of cortical neurons). 2
Map of body surface in the somatosensory cortex MAP OF BODY SURFACE IN THE MOTOR CORTEX 3
Development of retinotopic map Retina Tectum N T R C Topographic Mapping of Retinotectal Projections EphA3 Ephrin-A2 development Initial development of the map is activityindependent, require guidance of matching molecular gradients in the retina and tectum (ephrin Eph receptor interaction) ganglion cell Refinement of the map requires activity: Nearby retinal ganglion cells fire in a correlated manner, leading to stabilization of their connections to the tectal cell which is triggered to fire synchronously by these inputs, while distant cells fire in an uncorrelated manner, leading to elimination of their connection. tectal cell Plasticity of rat somatosensory cortex Barrel Cortex receiving sensory inputs from whiskers Depriving sensory inputs by removing whisker shrinkage of corresponding barrels -- Importance of normal sensory inputs even in adult -- Activity-dependent competition exists in adult cortex Barrel cortex Functional changes in V1 due to scotoma (blind spot) Visual field is represented by the grid on the retina, with corresponding maps shown on V1. Lesion of retina first silenced the corresponding cortical area, but reorganization of the receptive fields of cortical neurons leads to increased representation of the areas around the lesion and reduced representation of the lesioned area. (Gilbert and Wiesel) Artificial scotoma Deprivation of visual input to specific region of retina without lesion results in similar reorganization of the cortical receptive fields. 4
Functional expansion of cortical representation by repetitive use Monkey was trained in a task that required heavy usage of digits 2,3,4 --expansion of cortical representation of these digits after a few months Functional changes in the somatic sensory cortex of an owl monkey following amputation of a digit. Question remains to be answered: Are functional changes due to structural changes in the connectivity between neurons, or simply silencing of synaptic transmission, e.g., long-term depression or increased inhibition? Use-dependent changes in synaptic functions Long-term potentiation (LTP) and Long-term depression (LTD) -- Persistent increase or decrease in synaptic response due to repetitive activity, found in all regions of the brain -- Brief high-frequency stimulation LTP Prolonged low-frequency stimulation LTD -- Spike-timing dependent plasticity: A revised version of Hebb s hypothesis Both LTP and LTD are induced by repetitive correlated firing of pre- and postsynaptic cells, depending on the order of firing pre before post LTP post before pre LTD 5
Developmental vs. adult plasticity 1. Are these two forms of plasticity depend on similar synaptic mechanisms? Evidence: -- Development of ocular dominance columns is prevented by blocking NMDA receptors. (M. Constantine-Paton) -- Critical period plasticity (ocular dominance modification due to monocular deprivation) can be revived in adult primary visual cortex by protease treatment (that removes extracellular matrix around neurons). (L. Mafei) -- LTP/LTD can be induced in developing and adult cortex by similar stimulation. -- LTP/LTD induction can result in structural changes at synapses, presumably also changes in connectivity LTP increase spine formation, swelling of existing spines LTD shrinkage and retraction of spines 2. Do learning and memory in adult brain involves processes similar to activity-dependent developmental refinement of connections? Evidence: -- LTP is required for spatial learning (hippocampus) and fearing conditioning (amygdala) in rats -- LTP/LTD induction is accompanied by structural changes at synapses -- Neruotrophins required for developmental refinement of connections (e.g., in ocular dominance segregation) is also required for LTP induction in adult brain. Neurotrophins Awakening of Developmental Plasticity in Adult Brain Pizzorusso, T., L. Maffei, et al. Reactivation of Ocular Dominance Plasticity in the adult visual cortex. Science, 298: 1248 (2002) Removal of sidechains from chondroitin sulfate proteoglycans (CSPGs) by chondroitinase ABC partially restores ocular dominace plasticity to monocular deprivation in older animals after the critical period. McGee, A. W., Daw, N.W. & S.M. Strittmatter. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science, 309: 2222 (2005) In NgR -/- mice, visual cortex continues to exhibit full ocular dominance plasticity to 4d monocular deprivation well into adult. 6
Summary Experience-Dependent Plasticity in Circuit Formation 1. The formation of neural circuits in the developing brain depends not only on molecular cues for initial cell-cell recognition and synapse formation, but also on experience (activity)-dependent refinement of the connectivity. 2. While the extent of experience-dependent circuit refinement reduces drastically after the critical period, developmental plasticity can be revived in the adult brain. 3. The same molecular mechanisms that shut down the critical period plasticity may be responsible for preventing regeneration of neural circuits in the adult brain after injury. 4. The mechanisms underlying the experience-dependent circuit formation may be similar to those underlying learning and memory. 7