Transcript 投影片 1
Cell communication III: the nerve system 3-28-2016 Nature 510: 38; 2014. Resting membrane potential is maintained by Na-K ATPase and ATP hydrolysis 5 6 7 Two characteristics of action potential of neuron All or none; Unidirectional! 9 The refractory period after opening of voltage gated ion channel makes unidirectional propagation of action potential Conduction of the Action Potential • All-or-None Law – the principle that once an action potential is triggered in an axon, it is propagated, without decrement, to the end of the fiber • Rate Law – the principle that variations in the intensity of a stimulus or other information being transmitted in an axon are represented by variations in the rate at which that axon fires 11 12 13 Schwann cell is responsible for myelination of peripheral neuron Why different cell type for myelination in CNS and PNS? 14 • Transmission of this message, hopping from node to node, is called saltatory conduction, from the Latin saltare, “to dance.” • Saltatory Conduction – Conduction of action potentials by myelinated axons: the action potential appears to jump from one node of Ranvier to the next. 16 18 19 20 21 22 23 Most of neurotransmitter receptor are ligand gated ion channel 26 EPSP: excitatory postsynaptic potential 27 28 How to terminate the postsynaptic signaling? • The neurotransmitter is degraded by the enzyme in postsynaptic terminal. – Acetylcholinesterase inhibitors in Alzheimer’s disease • The neurotransmitter is dissociated from the receptor and reuptake by presynaptic transporter. – Prozac is the blocker of presynaptic serotonin transporter The cortex has ~109 neurons. Each Neuron has up to 104 synapses Spine 32 Central Hypothesis of learning – Synaptic plasticity • Synaptic plasticity – Changes in synaptic structure and biochemistry • Long-term potentiation (LTP) – Change in the strength of synaptic connections – Results from repeated activation Aplysia • 20,000 neurons in the CNS • The gill-withdrawal reflex, can be modified by • five different forms of learning: – habituation, – dishabituation, – sensitization, – classical conditioning, – operant conditioning. Why? Sensitization Pathway Release more serotonin at presynaptic terminal Long-term sensitization of the gillwithdrawal reflex of Aplysia leads to two major changes in the sensory neurons of the reflex (learning and memory) Persistent activation of protein kinase A Structural changes in the form of the growth of new synaptic connections. Long-term memory in Aplysia modulates the total number of varicosities of single identified sensory neurons PNAS 85, pp. 2373-2377, 1988 Long-term sensitization of the gill-withdrawal refex in Aplysia involves posttranslational modifications and alterations in protein synthesis. Two major memory systems in the brain: declarative (explicit) and procedural (implicit) Hebb’s Postulate “When an axon of cell A is near enough to excite a cell B and repeatedly and persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.” Donald Hebb, “Organization of Behavior”, 1949 Classical Conditioning Hebb’s rule Ear A Nose B Tongue D. O. Hebb (1949) Synaptic Plasticity Synaptic efficacy (strength) is changing with time. Many of these changes are activity-dependent, i.e. the magnitude and direction of change depend on the activity of pre- and postsynaptic neuron. Some of the mechanisms involved: - Changes in the amount of neurotransmitter released. Biophysical changes in ion channels. Morphological alterations of spines or dendritic branches. Modulatory action of other transmitters. Changes in gene transcription. Synaptic loss or sprouting. LTP: long term potentiation Typical LTP experiment: record from cell in hippocampus area CA1 (receives Schaffer collaterals from area CA3). In addition, stimulate two sets of input fibers. LTP Typical LTP experiment: record EPSP’s in CA1 cells (magnitude) Step 1: weakly stimulate input 1 to establish baseline Step 2: give strong stimulus (tetanus) in same fibers (arrow) Step 3: continue weak stimulation to record increased responses Step 4: throughout, check for responses in control fibers (input 2) LTP LTP is input specific. LTP is long-lasting (hours, days, weeks). LTP results when synaptic stimulation coincides with postsynaptic depolarization (achieved by cooperativity of many coactive synapses during tetanus). The timing of the postsynaptic response relative to the synaptic inputs is critical. LTP has Hebbian characteristics (“what fires together wires together”, or, in this case, connects together more strongly). LTP may produce synaptic “sprouting”. NMDA receptors and LTP • LTP relies on calcium influx at NMDA glutamate receptors • Calcium channels controlled by the NMDA receptor are blocked by a magnesium ion – Magnesium ion is ejected by: 1. simultaneous glutamate binding AND 2. depolarization of the post-synaptic cell (by activity at AMPA receptors on the membrane) 3. Calcium enter the cell and is critical to establishing LTP Strengthening synapses • Dendritic spike – an action potential results in a backwash of depolarization up the cell body and dendrites • Dendritic spike + glutamate binding at NMDA receptor = calcium channels open to allow calcium influx Strengthening synapses • Three synaptic modifications will support LTP – Addition of receptors – Addition of synapses – Increased glutamate release from the presynaptic membrane Synaptic modifications supporting LTP – Increased receptors • Individual synapses are strengthened by an increase in AMPA receptors on the post-synaptic membrane – Increases the cell’s response to glutamate release Hypothesized mechanism: 1. Calcium activates the CaMK enzyme 2. Activated CaMK binds to an intracellular portion of the NMDA receptor 3. Linking proteins bind to the CaMK 4. AMPA receptors bind to the linking proteins and are embedded into the cell membrane Synaptic modifications supporting LTP – Synaptogenesis • LTP results in the multiplication of synapses – Most synapses are located on dendritic spines – LTP results in division and multiplication of these spines Mechanism: 1. Postsynaptic density expands until it splits into multiple densities 2. Following perforation, the presynaptic active zone splits into corresponding regions 3. Perforated synapse further divides, until the spine branches 4. Branched spine ultimately becomes two spines, each containing a synaptic region Synaptic modifications supporting LTP – Synaptogenesis • Results in the terminal button of one presynaptic neuron synapsing with multiple spines on the postsynaptic neuron – Increases communication potential between the two cells • Threefold increase in synapses has been found experimentally Synaptic modifications supporting LTP – Presynaptic changes • LTP is associated with an increase in glutamate release by the presynaptic neuron – Influenced by retrograde messengers Nitric oxide – major retrograde signal from NMDA receptors to the presynaptic membrane NO is synthesized in the postsynaptic membrane in response to calcium influx Unstable and short-lived, can only diffuse across the synapse before breaking down Acts as a limited, direct messenger Long-term depression • Opposite of LTP, long-term depression is a long-lasting weakening of synapses that are not associated with strong inputs/production of action potentials – Seen when two inputs are stimulated at significantly different times, or when a synapse is activated while a cell is weakly depolarized or hyperpolarized – Results in the removal of AMPA receptors from the synapse • Weakening of synaptic strength may be necessary when new learning eliminates the need for previously established synaptic modifications – Ex. Remembering a new locker combination Synaptic connections between neurons are not immutable but can be modified by learning and that those anatomical modifications serve as elementary components of memory storage. Memory storage depends on neural architecture but not on specialized memory neurons. Different place cells could be active in different places and the combination of activity in many place cells created an internal neural map representing a particular environment The grid pattern had not been seen in any brain cells before! The grid cells were part of a path integration system and provided a solution to measuring movement distances and added a metric to the spatial maps in hippocampus. Hippocampus contains an inner map that can store information (learning and memory) about the environment! London taxi drivers had significantly larger hippocampal volume than control subjects! Acquiring "the Knowledge" of London's layout drives structural brain changes. Current. Biology, 21, 2109-2114; 2011 How memories of spatial routes achieved during active navigation are consolidated? Groups of place cells that are activated in a particular sequence during the behaviour display the same sequence of activation in episodes during the subsequent sleep.