Synaptic Rearrangement Objectives: At the end of this lecture, you should be able to perform the following on a written examination. 1.Identify the series of events leading to the elimination of all but one neuromuscular synapse at developing motor endplates. 2.Define the salient features of a critical period in developmental neurobiology. Give examples from the development of the visual system. 3.Identify the roles played by NMDA receptors and neurotrophins in the formation of ocular dominance columns. 4.Compare and contrast the remodeling of synaptic connections in the visual system and the neuromuscular junction.

Neuromuscular Synapses are Eliminated During Postnatal Development At birth, nearly all muscle fibers are polyneuronally innervated. During the next two weeks, all but one of these synaptic inputs is lost.

Neuromuscular Synapses Compete for Survival Synchronous electrical activity accelerates elimination, synchronous paralysis delays it. Application of excesses of different neurotrophic molecules prolongs polyneuronal innervation Several pathways may exist that help mediate competition Nature of competition may be more like a judged contest than like a race.

Neuromuscular Synapse Elimination is Gradual and Asynchronous Any competition between inputs is resolved at the level of individual synapses Multiple Innervation Terminal Segregation Branch Withdrawal Axon Retraction Keller-Peck et al, Neuron 31: , 2001

Synapse Elimination Involves Synaptic Takeover The surviving input takes over the synaptic space formerly occupied by the losing input(s). Walsh & Lichtman, Neuron 37: 67-73, 2003

Synapse Elimination is a Balance of Anterograde and Retrograde Signals

Proposed Functions of Synapse Elimination 1.Provides a way to ensure that each muscle fiber is innervated. 2.Allows axons of different motoneurons to capture a number of cells appropriate to its size. 3.Provides a means by which normal function can change the strength of synaptic connections. Gatesy & English, Dev. Dyn. 196: , 1993 Adult muscles are partitioned into neuromuscular compartments – exclusive innervation territories. In the absence of competition, cross compartmental inputs will form in neonates but not adults Synapse elimination completes the specific innervation of neuromuscular compartments

Anatomy of the Visual System Both eyes project to each visual cortex, but at the primary visual area (17), they remain largely segregated into ocular dominance columns.

Effects of Neonatal Monocular Deprivation Many cells in visual cortex remain responsive to inputs from both eyes after binocular deprivation. Development of proper circuitry depends on proper balance of inputs from two eyes Monocular deprivation in adult has no effect Normally, most cells receive visual inputs from both eyes, but not equally After MD as neonates, very few cells receive inputs from the closed eye

Effects of Monocular Deprivation Are Noted Anatomically Sensory deprivation early in life can alter the structure of the cerebral cortex.

Rudimentary Ocular Dominance Columns Develop in the Absence of Visual Inputs Columns in layer 4a of primary visual cortex with appropriate eye-specific inputs are present before the critical period for ocular dominance column plasticitiy. Columns develop in the absence of visual system input and before the development of retinal photoreceptors. Columns are not altered by visual deprivation. Full development of columns occurs later, and can be seen as a refinement of these primitive columns. Cowley & Katz, Curr. Opin. Neurobiol. 12: , 2002 Differences from earlier studies is thought to be a matter of technique.

Ocular Dominance Columns are Organized After Birth This synaptic rearrangement is brought about by axon retraction and local outgrowth of geniculate neurons.

Synchronous Activity From Each Eye Organizes the Ocular Dominance Columns Blocking activity in both eyes with TTx or synchronous stimulation of both optic nerves block formation of ocular dominance columns. Asynchronous activity leads to formation of ocular dominance columns. Normal development depends on competition for acquisition of synaptic partners This competition is emphasized in three-eyed frogs.

NMDA Receptors Mediate Competition Cooperative activity of afferent neurons from one eye are thought to depolarize target neurons sufficiently to release Mg block of NMDA receptor, allowing Ca influx. NMDA receptor acts as a coincidence detector of the activity of neurons from a single source. They support one aspect of the theory of learning proposed by Hebb. An additional retrograde signal to the presynaptic neuron is required.

Presynaptic Activity May Enhance Release of Neurotrophins From Target Neurons Neurotrophins could form such a retrograde signal. Excess of trk B ligands removes the ability of NMDA receptors to mediate competition. trkAtrkBtrkCp75 NTR BDNFNT-4NT-3NGF Finney & Shatz, J. Neurosci.18: , 1998 NO, another retrograde signaling molecule is not required for formation of ocular dominance columns.

Model of Synaptic Rearrangements