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SYNAPSE HISTORYThe term was introduced at the end of the nineteenth century by the British neurophysiologist Charles Sherrington, who argued, on the basis of his own observations of reflex responses and the studies of the great Spanish anatomist, Ramón Cajal, that a special form of transmission takes place at the contact between one cell and the next. • Santiago Ramon y Cajal- (late 1800‘s- early 1900s) using Golgi’s stain identified “dispositions of engagement” and proposed that the Cell Theory holds for neural tissue • Sherrington (physiologist) and others (1897) argued that nerve endings are only in contact with other neurons- help coin the term “synapse” • Studies followed that further described neuron components- axons (“axis cylinder”) and dendrites (“protoplasmic prolongations”) • 1950’s Intracelluar recordings and electron microscopy - Katz and others- Physiology of cholinergic transmission at NMJ (Nobel Prize, 1970) - Gray - Type I (assymetrical) and Type II synapses (symmetrical)

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DEFINITION: The synapse is the functional junction between two neurons. TYPES OF SYNAPSES: Depending on the manner an axon terminates on the other neurons, the synapses can be of following types: ANATOMICAL TYPES: 1 AXO-DENDRITIC: synapse between axon of a neuron and dendrite of another neuron. Eg: excitatory synapse in cerebral cortex, climbing fibres in cerebellum, etc 2 AXO-SOMATIC: synapse between axon of a neuron and soma of another neuron. Eg: BC in cerebellum, autonomic ganglia 3 AXO-AXONIC: synapse between axon of a neuron and axon of another neuron. Eg: synapse between mitral and granule cell in olfactory bulb.

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2 ELECTRICAL SYNAPSES: transmission occurs through gap junctions. It is similar to the process of nerve conduction. They conduct in both the directions. Eg: seen in retina and olfactory bulb. It is found mainly in invertebrates and lower vertebrates. 3 CONJOINT SYNAPSE: both chemical and electrical transmission occurs. PHYSIOLOGICAL TYPES: 1 CHEMICAL SYNAPSES: transmission is carried out by neurotransmitter. Most of the synapses are of this type. They conduct information only in one direction. These are more vulnerable to fatigue on repeated stimulation. They are of two type, type 1 and type 2.

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STRUCTURE OF A CHEMICAL SYNAPSE: 1 SYNAPTIC KNOB: as the axon of the neuron approaches the synapse, it loses the myelin sheath and divides into a number of fine branches which end in small swellings called synaptic knobs or buttons. Each synaptic knob contains large no. of mitochondria and synaptic vesicles containing neurotransmitter. Besides neurotransmitter the vesicle also contain other proteins to bind the neurotransmitter to the vesicle. 2 PRE-SYNAPTIC MEMBRANE: axonal membrane lining the synaptic knobs. On the inner aspect are present the zones of dense cytoplasm. 3 SYNAPTIC CLEFT: it is a small gap between pre and post synaptic membranes. It is filled by extra cellular fluid containing some glycoproteins. Enzymes are present in this cleft, which destroy the neurotransmitter. 4 POST-SYNAPTIC MEMBRANE: on the inner aspect there is a zone of dense cytoplasm. It contains large no. of receptor proteins which protrude out in the synaptic cleft.

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5 RECEPTOR PROTEINS: They have two components: BINDING COMPONENT and IONOPHORE COMPONENT 1 ION CHANNEL: allows passage of specified type of ions through the channel 2 SECOND MESSENGER ACTIVATOR: it is not an ion channel but instead protrudes into the cell cytoplasm and activates one or more substances inside the post synaptic neuron. FEATURES OF TWO TYPES OF CHEMICAL SYNAPSES:

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-one of the most prevailing types in neurons uses a group of proteins called G-PROTEINS -The G-PROTEIN in turn consists of 3 components:(a) alpha component that is activator portion(b) beta component and © gamma component that attach the G-PROTEIN to the inside of the cell membrane-On activation by a nerve impulse, the alpha portion separates and then it is free to move in the cytoplasm-In the cytoplasm of the cell, the separated alpha component performs one or more of the multiple functions: 1 opening specific ion channels 2 activation of cAMP or cGMP 3 activation of one or more intracellular enzymes 4 activation of gene transcription

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PROCESS OF CHEMICAL SYNAPTIC TRANSMISSION: A RELEASE OF NEUROTRANSMITTER: Action potential reaches the synaptic cleft depolarization of the pre synaptic terminal voltage gated Ca+2 channels open up increases the permeability of pre synaptic membrane to Ca+2 ions Ca+2 ions enter the axon terminal stimulates the sliding of vesicles towards pre synaptic membrane exocytosis of vesicles releasing neurotransmitter in the synaptic cleft transmitter release starts in 200-500 microsecs -for the transmitter to be effective on the post synaptic neuron requires proximity of release to the post synaptic receptors -this organization depends in part on NEUREXINS, proteins bound to the membrane of pre synaptic neuron that bind neurexin receptors in the membrane of the post synaptic neuron

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-In vertebrates neurexins are coded by a single gene but in mice and humans they are encoded by three genes -each of the genes have two regulatory regions and extensive alternating splicing hence around 1000 different neurexins are produced -the synaptic vesicles for fusing with the cell membrane involve V-SNARE protein SYNAPTOBREVIN in the vesicle membrane locking the T-SNARE protein SYNTAXIN in the cell membrane -transmitter diffuses through the cleft and binds with the receptors on post synaptic membrane -the time lapse occurring between arrival of nerve impulse and effect of neurotransmitter on post synaptic membrane is called synaptic delay.

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B DEVELOPMENT OF EXCITATORY POST SYNAPTIC POTENTIAL (EPSP) AND INHIBITORY POST SYNAPTIC POTENTIAL (IPSP): Both excitatory and inhibitory receptors exist on the post synaptic membrane. EXCITATORY POST SYNAPTIC POTENTIAL: Excitatory post synaptic potential (EPSP) i.e. depolarization of post synaptic membrane is produced by the excitatory neurotransmitters. -The most common excitatory neurotransmitter in CNS is Glutamate. -the initial depolarizing response produced by a single stimulus to proper input begins about 0.5ms after the afferent impulse enters the spinal cord -it reaches its peak 1-1.5ms later and then declines exponentially -during this potential, excitability of the neuron to other stimuli is increased, and consequently the potential is called EPSP

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Recording of EPSP : it can be studied by inserting a micro electrode into the ventral horn cell of the spinal cord and stimulating the sensory nerve fibers in the dorsal root. Ionic basis of EPSP : -Excitatory neurotransmitter binds with a specific protein and opens the ligand- gated Na+ channels on the post synaptic membrane. -Na+ ions diffuse inward and depolarize the membrane. -the amount of Na+ influx is able to produce only a brief depolarization followed by a slower decline to the resting potential. Conduction of EPSP : it does not transmit over the cell but it can depolarize the adjacent membrane. Summation of EPSP : it is a graded response and it shows temporal and spatial summation. It does not follow all or none law.

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INHIBITORY POST SYNAPTIC POTENTIAL: Inhibitory post synaptic potential i.e. hyper polarization of the post synaptic membrane is produced by the inhibitory neurotransmitters released in the synaptic cleft. -The most common inhibitory neurotransmitter in the CNS is Glycine and GABA. -like EPSP they peak 1-1.5ms after the stimulus and decrease exponentially with a time constant of about 3ms -during this potential, the excitability of neuron to other stimuli is decreased, consequently it is called IPSP Ionic basis of IPSP : -The inhibitory neurotransmitter causes opening of K+ channels or Cl- channels in the post synaptic membrane. -large no. of K+ ions diffuse from the neuron to the extra cellular fluid or large no. of Cl- ions diffuse to the interior of the neuron. -so the post synaptic membrane becomes more negative

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C IN ACTIVATION OF THE NEUROTRANSMITTER FROM THE SYNAPTIC CLEFT: Neurotransmitter can be in activated in the following three ways: Diffusion of the transmitter out of the cleft 2. Enzymatic degradation of the transmitter 3. Active transport back into the pre synaptic terminal. -the amount of neurotransmitter present in the synaptic knob is exhausted within few seconds to few minutes of neuronal activity. -synthesis of transmitter at the nerve terminal goes on continuously. Recording of the IPSP: method for recording IPSP is same as that of EPSP. Summation of IPSP : Spatial and temporal summation occurs.

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D DEVELOPMENT OF ACTION POTENTIAL: 1SYNAPTIC INTEGRATION: -It refers to the summation of both EPSP and IPSP produced at the post synaptic membrane. -It is the net summated potential which determines whether synaptic transmission will occur or not. 2GENERATION OF INITIAL SEGMENT SPIKE: -the summated potential spreads passively to the initial segment which comprises axon hillock and the proximal part of unmyelinated nerve fibers. -if the summated potential is large enough to depolarize the initial segment of neuron to threshold level of about 6-10 mV, a spike potential called the initial spike is generated. -the magnitude of IS is 30-40-mV from the threshold level.

3 GENERATION OF PROPOGATED SIGNALS i.e. ACTION POTENTIAL: -the initial spike requires a relatively low degree of depolarization for its own production, but once initiated, it itself produces a further depolarization of 30-40 mV by opening voltage gated channels on the axon hillock.-thus the initial spike triggers the generation of action potential which travels in both the directions. : 

3 GENERATION OF PROPOGATED SIGNALS i.e. ACTION POTENTIAL: -the initial spike requires a relatively low degree of depolarization for its own production, but once initiated, it itself produces a further depolarization of 30-40 mV by opening voltage gated channels on the axon hillock.-thus the initial spike triggers the generation of action potential which travels in both the directions.

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INHIBITION AT SYNAPSES: Four different types of inhibition are known to occur at the synapses in the CNS: 1 POST SYNAPTIC INHIBITION: Inhibition of the post synaptic membrane can occur by the following ways: 1 By development of IPSP also called DIRECT INHIBITION: -one eg is afferent fibres from the muscle spindles in the skeletal muscle are known to pass directly to the spinal motor neurons of the motor units supplying the same muscle -impulses in this afferent pathway cause EPSPs and summation, propogated responses in the post synaptic motor neurons -at the same time IPSPs are produced in the motor neurons supplying the antagonistic muscles -this later response is mediated by branches of the afferent fibres that end on GOLGI BOTTLE NEURON -these inter neurons secrete inhibitory NT GLYCINE at synapses of the motor neurons that supply the antagonistic muscles -this phenomenon is also called RECIPROCAL INNERVATION

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2 Without development of IPSP: -due to short circuiting mechanism -in some neurons the conc. Differences for K+ and Cl- ions are such that the NP of these ions are equal to the RMP of the neuron -so no net transfer of ions in either direction and no EPSP can develop -but when the neuron is excited through other synapse causing inflow of Na+ ions, the rapid flux of K+ and Cl- ions would nullify the EPSP produced -this tendency of K+ and Cl- ions to maintain the potential to RMP level masks the effect of Na+ flow by the excitatory synapse, thus causing inhibition 3 Due to refractory period -sometimes the post-synaptic membrane can be refractory to excitation because it has just fired and is in its refractory period; i.e. existing EPSP has still not been cleared.

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2 PRE SYNAPTIC INHIBITION: Also known as indirect inhibition as IPSP is not generated. It can occur in the following ways: 1 By opening Cl- channels of pre synaptic terminal: -inhibitory neuron(C) releases an inhibitory NT(GABA), that binds to GABA gated Cl- channels on the pre synaptic neuron terminal(A) -increase in Cl- permeability results in hyper polarization of the pre synaptic axonal terminal(A) -when AP arrives at the pre synaptic terminal, the size of AP is reduced because of increased Cl- conductance -so less Ca+2 enters the nerve terminal and amount of excitatory neurotransmitter released is decreased markedly.

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2 By activation of G protein: -inhibitory NT GABA is released from the inhibitory neuron ( C ) and it binds to a receptor called GABA receptor, it activates G-protein -G-protein aids in reducing the excitatory NT released from pre-synaptic terminal(A)by acting in one of the following ways: A By opening K+ channels: The G protein may open K+ channels that reduce the size of AP reaching the nerve terminal by hyper polarizing the pre-synaptic membrane. B By directly blocking the Ca+2 channels: The G protein may directly block the opening of Ca+2 channels that normally occurs when the AP reaches the nerve terminal; so less Ca+2 enters the pre-synaptic terminal and the amount of excitatory NT release is diminished.

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3 FEED BACK INHIBITION: -It is also known as RENSHAW CELL INHIBITION. -It is known to occur in spinal alpha motor neurons through an inhibitory inter neuron. -In feedback inhibition a neuron inhibits those very neurons that excite it. i.e. a neuron is inhibited by its own output. -In this way firing of an AP by a motor neuron is followed by a phase of hyper-polarization of not only the same motor neuron but also many others in the neighbourhood. -It is basically a post synaptic inhibition but classified separately because the inhibitor RENSHAW CELLS are activated by a collateral of the ventral horn cell rather than an afferent neuron. -This type of inhibition is also seen in other parts of CNS. It limits the excitability of the motor neurons.

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4 FEED FORWARD INHIBITION: -It is seen in cerebellum. -In this type of inhibition a neuron is connected through two pathways: one excitatory and other inhibitory. -EG: in cerebellum, the Granule cell (Gr C) excites the Purkinje cells (PC) which is soon inhibited by the Basket cell (BC), which in turn was also excited by the Granule cell (Gr C). This type of arrangement limits the duration of excitation produced by any given afferent volley, i.e. it allows a brief and precisely timed excitation. SIGNIFICANCE OF SYNAPTIC INHIBITION: -It offers a type of restriction over neurons and muscles to react properly and appropriately. -It helps to select exact number of impulses and to omit or block the excess ones.

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PROPERTIES OF SYNAPTIC TRANSMISSION 1 ONE WAY CONDUCTION: -The chemical synapse allows only one way conduction of an impulse, i.e. from pre-synaptic neuron to post synaptic neuron and never in opposite direction. This is called Law of Dynamic Polarity. CAUSE: Only the pre-synaptic nerve terminal contains the chemical NT, whereas the post synaptic membrane contains specific receptor sites. SIGNIFICANCE: the axons can conduct impulses in either direction with equal ease. 2 SYNAPTIC DELAY: -It refers to a time lapse which occurs between arrival of a nerve impulse at the pre-synaptic terminal and its passage to the post-synaptic membrane. -It occurs by approximately 0.5ms.

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CAUSE: -Time taken for the release of NT. -Time taken for the diffusion of NT through the synaptic cleft to the post-synaptic membrane. -Time taken for the action of NT to bind with receptors on the post-synaptic membrane and to cause the opening of the ion channels. -Time taken for the diffusion of the ions causing changes in the resting membrane potential (RMP). SIGNIFICANCE: it is one of the causes for the latent period of the reflex activity. Also the number of neurons involved in the reflex can be estimated from the duration of reaction time of a reflex action. 3 SUMMATION: A synapse exhibits property of both temporal and spatial summation of EPSP and IPSP. SIGNIFICANCE: excitation of a single pre-synaptic neuron never excites or inhibits the post synaptic neuron as sufficient NT is not released. Hence the property of summation is essential for stimulation of the post-synaptic membrane either by simultaneous stimulation or by repeated stimulation.

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4 CONVERGENCE: -It refers to the phenomenon of termination of signals from many sources (i.e. many pre-synaptic neurons on a single post-synaptic neuron). -Eg. Ventral horn cells of the spinal cord receive convergent signals from the cortico-spinal tract, reticulo-spinal tract, rubro-spinal tract and sensory afferent from dorsal root. 5 DIVERGENCE: -one pre-synaptic neuron may terminate on many post-synaptic neuron. i.e. single impulse is converted into a no. of impulses going to a no. of post-synaptic neurons which may travel in same tract or multiple tracts. This causes magnification and therefore helps in amplification of an impulse.

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6 OCCLUSION PHENOMENON: -The response to stimulation of two pre-synaptic neurons is less than the sum total of the response obtained when they are stimulated separately. -This happens because some post-synaptic neurons are common to both the pre-synaptic neurons. -Thus occlusion is due to overlapping of afferent fibres in their central distribution.

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7 SUBLIMINAL FRINGE: -An afferent nerve fibre divides into many hundred branches. -Of these, a large number may terminate on one efferent neuron, while a smaller number terminate on other efferent neuron lying nearby. -When afferent neuron is stimulated the efferent neuron which has many pre-synaptic terminals are excited to threshold level and AP is fired. -Others in the peripheral zone are excited to only sub-threshold level. This is known as subliminal fringe effect. -Thus, the post-synaptic neurons that are fired are in discharging zone and those which are not fired are said to be in subliminal fringe. SIGNIFICANCE: As a result of summation, occlusion and subliminal fringe effect, the patterns of impulses in peripheral nerves are usually altered as they pass through synapses on the way to brain. One such effect is phenomenon of referred pain.

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8 FACILITATION: -When pre-synaptic axon is stimulated with several consecutive individual stimuli, each stimulus may evoke a larger post-synaptic potential than that evoked by previous stimulus. MECHANISM: -Each succeeding stimulus increases the duration of AP in pre-synaptic neuron. So voltage gated Ca+2 channels can remain open for a prolonged period. -Normally subliminal stimulus from a pre-synaptic neuron primes the post-synaptic neuron. -So that another subliminal stimulus can evoke a discharge from the post-synaptic neuron. -Hence first stimulus is supposed to facilitate the effect due to prolonged exposure of post-synaptic neuron to the NT.

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9 SYNAPTIC FATIGUE: -When the pre-synaptic neuron is stimulated separately, the rate of impulse discharge in the post-synaptic neuron is initially high but within a few seconds there occurs a gradual decrease and finally disappearance of the post-synaptic response. -This phenomenon is called synaptic fatigue or habituation. -It is a temporary phenomenon. MECHANISM: -Due to exhaustion of chemical NT. -At high rate of chemical transmission the synthesis of NT fails to keep pace with rate of release at pre-synaptic terminals. Other factors contributing to fatigue are as follows: Gradual inactivation of Ca+2channels which decrease the intra cellular Ca+2. -Accumulation of waste products. -Refractiveness of post-synaptic membrane to transmitter substance.

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10 SYNAPTIC PLASTICITY AND LEARNING: -Plasticity refers to capability of being easily moulded or changed. -Plastic changes in synaptic transmission known are: (i)POST TETANIC POTENTIATION, ii) LONG TERM POTENTIATION, iii) SYNAPTIC FATIGUE OR HABITUATION, iv) SENSITIZATION and v) LOW FREQUENCY DEPRESSION. POST TETANIC POTENTIATION: -When a pre-synaptic neuron is stimulated with a single stimulus, followed by stimulation with a volley of stimuli (100/sec) for two seconds and then again with a single stimulus; the second stimulus evokes a larger post-synaptic response than the first stimulus. -This phenomenon is called post tetanic potentiation. -cause: a brief tetanizing stimuli in the pre-synaptic neuron results in an increase in intra cellular Ca+2 due to increased Ca+2influx.

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ii) LONG TERM POTENTIATION: -When the post tetanic potentiation gets much more prolonged and lasts for days, it is called long term potentiation. -cause: due to increase in intra cellular Ca+2 in the post-synaptic neuron. -This phenomenon commonly occurs in the HIPPOCAMPUS. iii) SENSITIZATION: -Prolonged occurrence of increased post-synaptic responses after a stimulus is paired once or several times with noxious stimulus. 11 REVERBERATION: -It refers to phenomenon of passage of impulse from pre-synaptic neuron and again back to pre-synaptic neuron to cause a continuous stimulation of the pre-synaptic neuron. -This causes reverberation of impulse through the same circuit again and again. -It is prevented to some extent by the phenomenon of fatigue.

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12 RECIPROCAL INHIBITION: -An afferent signal activates an excitatory neuron to a group of muscles -and simultaneously activates inhibitory signals to other, usually antagonistic muscles. 13 AFTER DISCHARGE: -It refers to the phenomenon in which a single instantaneous input results into sustained output signals. -Input signals lasts only for one millisecond and output signals last for many milliseconds.