PSL300 Lecture 06 - Blood Brain Barrier PDF

PSL300 PSL300 - Lecture 06 Blood Brain Barrier Ventricles CSF – Choroid Plexus Astrocytes – Local Blood Flow Blood-Brain Barrier The brain and the spinal cord are protected from the general circulation and the body The ionic composition of the extracellular fluid ar...

PSL300 PSL300 - Lecture 06 Blood Brain Barrier Ventricles CSF – Choroid Plexus Astrocytes – Local Blood Flow Blood-Brain Barrier The brain and the spinal cord are protected from the general circulation and the body The ionic composition of the extracellular fluid around the neuron must be carefully controlled: – Can not change the excitability of the membrane (e.g. with KCl injection > decreased K+ concentration gradient > depolarization > inactivation of the Na+ channel > no more AP produced) – Can not have neurotransmitters floating around for no reason Thus, the extracellular fluid in the neuronal environment (brain and spinal cord) are carefully regulated through Blood-Brain Barrier (BBB) Blood-Brain Barrier The brain and the spinal cord are protected from the general circulation and the body The ionic composition of the extracellular fluid around the neuron must be carefully controlled: – Can not change the excitability of the membrane (e.g. with KCl injection > decreased K+ concentration gradient > depolarization > inactivation of the Na+ channel > no more AP produced) – Can not have neurotransmitters floating around for no reason Thus, the extracellular fluid in the neuronal environment (brain and spinal cord) are carefully regulated through Blood-Brain Barrier (BBB)  Blood-Brain Barrier BBB can be thought of as a 2-fold entity: Between Blood Vessels & Interstitial Fluid and Blood Vessels & CSF Blood (capillaries) [Na+] 140 mEq/L [K+] 4.5 mEq/L [protein] 7 mg/dL Fluid bathing the neurons Interstitial fluid CSF (ventricles) Fluid in the ventricles [Na+] 140 mEq/L [K+] 2.8 mEq/L [protein] 35 mg/dL  Blood-Brain Barrier BBB can be thought of as a 2-fold entity: Between Blood Vessels & Interstitial Fluid - Blood Vessels & CSF Blood (capillaries) [Na+] 140 mEq/L [K+] 4.5 mEq/L [protein] 7 mg/dL Fluid bathing the neurons Interstitial fluid CSF (ventricles) Fluid in the ventricles [Na+] 140 mEq/L [K+] 2.8 mEq/L [protein] 35 mg/dL  Blood-Brain Barrier BBB can be thought of as a 2-fold entity: Between Blood Vessels & Interstitial Fluid - Blood Vessels & CSF Blood (capillaries) [Na+] 140 mEq/L [K+] 4.5 mEq/L [protein] 7 mg/dL Fluid bathing the neurons Interstitial fluid CSF (ventricles) Fluid in the ventricles [Na+] 140 mEq/L [K+] 2.8 mEq/L [protein] 35 mg/dL Blood-Brain Barrier Parkinson’s disease Blood-Brain Barrier MSG Areas Lacking the BBB Most of the brain is protected by BBB, but it is not continuous At some places it is essential for neurons to communicate freely with the blood stream (e.g. hypothalamus) The pituitary gland (releases hormones) is directly connected to the hypothalamus > thus, BBB is purposely broken to allow release of hormones In ‘Circumventricular organs’ (around 3rd ventricle) the BBB is broken so neurons can sense specific chemical [ ] Generally, BBB is broken in areas that interact with endocrine system or require sensitivity to metabolites in plasma Areas Lacking the BBB Most of the brain is protected by BBB, but it is not continuous At some places it is essential for neurons to communicate freely with the blood stream (e.g. hypothalamus) The pituitary gland (releases hormones) is directly connected to the hypothalamus > thus, BBB is purposely broken to allow release of hormones In ‘Circumventricular organs’ (around 3rd ventricle) the BBB is broken so neurons can sense specific chemical [ ] Generally, BBB is broken in areas that interact with endocrine system or require sensitivity to metabolites in plasma Brain Encasings Skull Meninges: – Dura mater (very tough membrane, sac containing the brain and the spinal cord) – Arachnoid membrane (much more delicate tissue) – Pia mater (lies right on top of the brain; tethered to Arachnoid by Arachnoid ‘Trabeculae’) – Between the arachnoid membrane and Pia matter > Subarachnoid space (filled with CSF) > brain floats to protect from mechanical stress Reticular formation Brain Encasings Skull Meninges: – Dura mater (very tough membrane, sac containing the brain and the spinal cord) – Arachnoid membrane (much more delicate tissue) – Pia mater (lies right on top of the brain; tethered to Arachnoid by Arachnoid ‘Trabeculae’) – Between the arachnoid membrane and Pia matter > Subarachnoid space (filled with CSF) > brain floats to protect from mechanical stress Reticular formation Brain Encasings Skull Meninges: – Dura mater (very tough membrane, sac containing the brain and the spinal cord) – Arachnoid membrane (much more delicate tissue) – Pia mater (lies right on top of the brain; tethered to Arachnoid by Arachnoid ‘Trabeculae’) – Between the arachnoid membrane and Pia matter > Subarachnoid space (filled with CSF) > brain floats to protect from mechanical stress Reticular formation Brain Encasings In the subarachnoid space, we have blood vessels > capillaries to the brain tissue > BBB, in between the capillaries and the brain tissue Filled with CSF Blood-Brain Barrier The endothelial lining of the BV, mostly contain large gaps (fenestrations), through which molecules can pass In Brain, endothelial cells are tightly bound leaving no gaps > this constitutes the BBB (everything has to be transported) Ventricles The ventricles are cavities deep inside the brain A large curving Lateral Ventricle (LV) inside each cerebral hemisphere, a paired structure across the midline Ventricles The LV empties into the 3rd Ventricle, right in the middle, deep in the brain under the cerebral hemisphere The 3rd Ventricle communicates via a channel called “Aqueduct of Sylvius” to the 4th Ventricle Ventricles From the 4th Ventricle, we have a canal, “Central Canal” which goes in the middle of the spinal cord All these ventricles are filled with CSF Ventricles CSF produced in the ventricle drains through the ventricle of the central canal CSF then moves to outer parts of the brain (subarachnoid space) and finally exits at the top of the brain into large venous sinus (on the midline) Ventricles Thus all the CSF eventually drains into either venous sinus or veins somewhere along the line About ½ CSF drains through ‘Arachnoid villi’ into the venous system Arachnoid Villi Arachnoid Villi is an out pouching of the arachnoid tissue, sticks out through the dura matter into the venous sinus > CSF drains into the venous system Ventricles Ventricles are filled with CSF, which is the bathing medium of brain (highly regulated ionic content, few macromolecules) CSF is produced from plasma by ‘choroid plexus’, which lines the ventricles (LV, 3rd, 4th, all have choroid plexus producing CSF) All the ventricles are filled with CSF (including the subarachnoid space, there is communication between the ventricles and the subarachnoid space) and eventually drains into the venous system Choroid Plexus Choroid Plexus produces most of CSF (but not all, some are produced in the capillaries inside the brain) Made up of epithelial cells connected by tight junctions Choroid Plexus produces CSF continuously (550 ml/day) to circulate cleansing mechanism Choroid Plexus is a dense network of capillaries ballooning out into the ventricular wall with tight junction so that everything has to be transported Cerebrospinal Fluid CSF is produced by ‘Choroid Plexus’ in ventricles CSF fills the ventricles and the subarachnoid space CSF has same osmolarity and [Na+] as blood Greatly reduced [K+], [Ca2+] and [Mg2+] Total volume on an average person is 215ml Cranial CSF is 140ml (25ml in ventricles, 115ml in subarachnoid space) and the spinal CSF is 75ml Thus, most of the CSF is in the subarachnoid space, serving as ‘cushion’ Cerebrospinal Fluid A lumbar puncture (spinal tap) is a diagnostic, therapeutic procedure > collect sample of cerebrospinal fluid (CSF) for analysis Astrocytes The walls of the capillaries are plastered with the ‘end feet’ of glial cells, particularly the astrocytes Astrocytes provide a bridge between neurons and blood vessels. Astrocytes The walls of the capillaries are plastered with the ‘end feet’ of glial cells, particularly the astrocytes Astrocytes provide a bridge between neurons and blood vessels. Astrocytes Astrocytes are efficient at glycolysis Astrocytes produce lactate as an end-product Lactate is a substrate for ATP production Astrocytes Astrocytes: – Remove neurotransmitters – Provide energy substrates for neurons and more They are following and latching on to BV (some end feet latched onto the BV and the others with neurons) Local Blood Flow Astrocytes also regulate local blood flow, but how? Astrocytes are already bridging the gap between BV and neurons, so they are in good spot to signal BV when to dilate and to constrict (increase or decrease blood flow) Astrocytes have connection with the neuron at the synapse and when they detect increased signaling, they can send a metabolic signal outward to BV (opposite to nutrient flow), signaling neuronal activity level Local Blood Flow Glutamate in synapses triggers Ca2+ release within astrocytes; Ca2+ wave travels through astrocytes and triggers prostaglandin (PGE2) release at end-foot PGE2 causes vasodilation > increased blood flow Local Blood Flow Glutamate in synapses triggers Ca2+ release within astrocytes; Ca2+ wave travels through astrocytes and triggers prostaglandin (PGE2) release at end-foot PGE2 causes vasodilation > increased blood flow Vasodilation Increased Calcium wave blood flow Thank You! PSL300 PSL300 - Lecture 05 Receptor Potential – Receptor Protein – Transmission of Signal – Adaptation – Habituation Coding of Stimulus Intensity Coding of Modality Receptive Field – Axon Reflex Receptor Potential Receptor potential: change in the MP due to receipt of signal from exterior sensory cue The energy from the environment will react with membrane proteins and in general this will cause depolarization Depolarization of sensory receptors upon receipt of specific energy Exception: photoreceptors hyperpolarize Receptor Potential Similar to PSP, the receptor proteins are embedded in sensory cell membrane The receptor proteins of the sensory cells will change shape when specific energy is received When the receptor protein changes shape, it can either: – Directly open ion channels (e.g. cation channels > leads to depolarization of the membrane) – Enzyme is activated via G-protein coupling > leading to production of 2nd messenger (cAMP, cGMP, InP3) > lots of 2nd messenger > amplifying the signal Receptor Potential Similar to PSP, the receptor proteins are embedded in sensory cell membrane The receptor proteins of the sensory cells will change shape when specific energy is received When the receptor protein changes shape, it can either: – Directly open ion channels (e.g. cation channels > leads to depolarization of the membrane) – Enzyme is activated via G-protein coupling > leading to production of 2nd messenger (cAMP, cGMP, InP3) > lots of 2nd messenger > amplifying the signal Receptor Potential Chemical stimulus binds to specific metabotropic receptor (G-protein coupled) > activation of G-protein > activate adjacent enzyme (adenyl cyclase) > produces 2nd messengers (cAMP) > cAMP activate kinases > directly interact with ion channels or phsophorylate other proteins Stages of Amplification There are 2 stages of amplification: – G-protein can activate a number of different enzyme molecules – Each of these enzyme molecules will produce lots of 2nd mesenger (cAMP) Thus, one stimulus molecule can produce lots of 2nd messenger (cAMP) Olfactory Receptor Specific receptor proteins bind specific odorant Olfactory Receptor Specific receptor proteins bind specific odorant Olfactory Receptor Specific receptor proteins bind specific odorant > activate G-protein > activate adynyl cyclase > production of cAMP > cAMP directly binds to ion channels > allow cations (Na+ and Ca++) to go through > depolarization of the membrane Olfactory Receptor The depolarizing current has to travel down the membrane and down to the trigger zone of the axon Trigger zone Olfactory Receptor The depolarizing current has to travel down the membrane and down to the trigger zone of the axon Amplification of the signal Trigger zone Sensory Cell Transmission Categories of sensory cell transmission: – Sensory cell generates an action potential at a spike-generating zone – Sensory cell releases vesicles when depolarized; impulses generated in post-synaptic neuron Transmission of Signal (AP) Located at the axon terminal (e.g. in the sensory axon innervating the skin). First patch of excitable membrane will generally be at the branch point; thus, the receptor potential will have to travel and generate summation at a branch point to reach threshold to get an AP Skin surface Transmission of Signal (AP) Located at the axon terminal (e.g. in the sensory axon innervating the skin). First patch of excitable membrane will generally be at the branch point; thus, the receptor potential will have to travel and generate summation at a branch point to reach threshold to get an AP Skin surface Passive spread Sensory Cell Transmission Categories of sensory cell transmission: – Sensory cell generates an action potential at a spike-generating zone – Sensory cell releases vesicles when depolarized; impulses generated in post-synaptic neuron Transmission of Signal (Vesicles) The depolarizing current don’t produce any AP > travel throughout the membrane and at the other end > they depolarize the membrane sufficiently > influx of Ca++ ions and trigger exocitosis vesicles > sensory cell is releasing vesicles and not producing an AP Taste Receptor AP travel throughout the membrane and at the other end > influx of Ca++ ions > vesicles released vesicles (not Inside mouth producing an AP) Taste Receptor AP travel throughout the membrane and at the other end > influx of Ca++ ions > vesicles released vesicles (not Inside mouth producing an AP) Taste Receptor AP travel throughout the membrane and at the other end > influx of Ca++ ions > vesicles released vesicles (not producing an AP) Adaptation The MP can decay over time leading to ‘Adaptation’ The original voltage is not sustained and it’s dropped over time, even though the stimulus may be constant Types of adaptations – Slowly Adapting – Rapidly Adapting Adaptation (Slow) Slowly-Adapting: receptor potential sustained for duration of stimulus Interested in overall magnitude of the stimulus Adaptation (Rapid) Rapidly-Adapting: receptor potential elicited by change in stimulus energy, decays to zero when stimulus is constant Interested in how quickly the stimulus is being delivered, the velocity of stimulus being delivered Adaptation (Rapid) Rapidly-Adapting: receptor potential elicited by change in stimulus energy, decays to zero when stimulus is constant Interested in how quickly the stimulus is being delivered, the velocity of stimulus being delivered Habituation Habituation is the response to successive stimuli in time Habituation: repeated stimuli (identical) in succession elicit progressively weaker responses Habituation response depends on the cell, some will show large degree and some won’t Coding of Stimulus Intensity The receptor potential they will vary directly in proportion with the intensity of the stimulus Greater the stimulus intensity > greater the receptor depolarization (graded potential) > more transmitter released and/or higher AP frequency The greater the depolarization > the faster the membrane will be brought up from hyperpolarization to generate a new spike The Impulse frequency will always be limited by the refractory period Coding of Stimulus Intensity The receptor potential they will vary directly in proportion with the intensity of the stimulus Greater the stimulus intensity > greater the receptor depolarization (graded potential) > more transmitter released and/or higher AP frequency The greater the depolarization > the faster the membrane will be brought up from hyperpolarization to generate a new spike The Impulse frequency will always be limited by the refractory period Coding of Stimulus Intensity After a while, you will reach a ceiling due to refractory period What if you want to do coding above this ceiling? The strategy is to recruit additional neurons As stimulus intensity increases, we recruit higher threshold sensory neurons Coding of Stimulus Intensity After a while, you will reach a ceiling due to refractory period What if you want to do coding above this ceiling? The strategy is to recruit additional neurons As stimulus intensity increases, we recruit higher threshold sensory neurons Post Synaptic Receptors Strategies to code for the strength of stimulus – Increase frequency of AP at excitable membrane ( intensity of stimulus >  frequency of AP [receptor A]) – With increasing stimulus strength, we recruit an additional receptor B, which has a higher threshold Receptor A Receptor B Post Synaptic Receptors Strategies to code for the strength of stimulus – Increase frequency of AP at excitable membrane ( intensity of stimulus >  frequency of AP [receptor A]) – With increasing stimulus strength, we recruit an additional receptor B, which has a higher threshold Receptor A Receptor B Coding for Modality How are we going to distinguish different modality (quality) of stimulus? We use a ‘Labeled Line’ strategy This means that activity in one pathway means a particular stimulus quality and nothing else Coding for Modality Within a modality, we could have a variety of stimulus qualities All sensations have sub-modalities that you could distinguish If you had to devise receptor proteins for ALL these qualities, it won’t be efficient Is there a better way? Population Code The answer is Population Code Population coding is coding using the ratio of activity from a restricted number of different receptor types Specific stimulus is coded by ratio of activity across the population of receptors Population Code A given receptor (e.g. A), type will respond to a wide range, but it has a peak and that is different from others Thus, any given stimulus (dotted line) will activate one receptor (C) very strongly but others (A, B) more weakly Receptor B Receptor C Receptor A Sensory Space Receptive Field Each sensory neuron is going to respond to a particular spatial area (e.g. skin, it’s the territory on the skin) > Receptive Field Receptive Field of a given sensory neuron is the territory in which you could activate that neuron Receptive Field is always defined in relation to a given sensory neuron, each sensory neuron will have a different Receptive Field Receptive Field Receptive Field in cutaneous sensory neuron is the skin territory in which adequate stimulation elicits a response and is generally about 10-20 mm across (in the fingertips, it can be as little as 1 mm across) Receptive Field Receptive Field in cutaneous sensory neuron is the skin territory in which adequate stimulation elicits a response and is generally about 10-20 mm across (in the fingertips, it can be as little as 1 mm across) Thank You! PSL300 PSL300 - Lecture 04 Post-Synaptic Receptors – Ionotropic Receptors – Metabotropic Receptors Spread of PSP PSP Summation – Spatial Summation – Temporal Summation Inhibitory Synaptic Potential AP Spike Train Transmitter Removal Post Synaptic Receptors Transmitter agent diffuses across synapse and binds to a specific site on a receptor protein embedded in postsynaptic membrane Binding of transmitter causes a change in shape of the receptor protein Receptors are either – Ionotropic (directly opens channels) – Metabotropic (initiates a metabolistic cascade to activate enzymes) Receptor determines the effect, not the transmitter Ionotropic Effects Ligand binding opens an ion channel > Ionotropic Binding of the transmitter to the post-synaptic membrane results in change in the post-synaptic membrane potential, this is called the Post-Synaptic Potential (PSP) The duration of PSP is about 20-40 ms (as long as the transmitters are present) Ion channel may be specific for cations (Na+, K+) > EPSP (depolarizing) Or ion channel may be specific for Cl- or K+ ion > IPSP (hyperpolarizing) Ionotropic Effects Nicotinic receptor for Acetylcholine Ionotropic Effects Nicotinic receptor for Acetylcholine Ligands for Ionotropic Receptors The ligands for the ionotropic receptors (transmitters that can act on ionotropic receptors) are principally: – Acetylcholine (Ach) – Glutamate – GABA – Glycine All these ligands can act on the metabotropic receptors; It’s the receptor that determines the effect and not the transmitter Ligands for Ionotropic Receptors The ligands for the ionotropic receptors (transmitters that can act on ionotropic receptors) are principally: – Acetylcholine (Ach) – Glutamate – GABA – Glycine All these ligands can act on the metabotropic receptors; It’s the receptor that determines the effect and not the transmitter Metabotropic Effects Binding of the ligand to the post-synaptic metabotropic receptor activates an enzyme that is usually G-protein coupled The enzyme facilitation will result in  (production) or destruction of 2nd messengers 2nd messengers are either cAMP, cGMP, or InP3 2nd messenger then activates other enzymes, e.g. phosphokinases which phosphorylate membrane proteins or other proteins in the cytoplasm If you phosphorylate membrane proteins (i.e. ion channels) > result in modulation of ion currents Metabotropic Effects Binding of the ligand to the post-synaptic metabotropic receptor activates an enzyme that is usually G-protein coupled The enzyme facilitation will result in  (production) or destruction of 2nd messengers 2nd messengers are either cAMP, cGMP, or InP3 2nd messenger then activates other enzymes, e.g. phosphokinases which phosphorylate membrane proteins or other proteins in the cytoplasm If you phosphorylate membrane proteins (i.e. ion channels) > result in modulation of ion currents Metabotropic Effects Ionotropic effect is much more immediate (opens ion channel directly) The metabotropic receptor activation takes time Moreover, it is not necessary that there is any change in the MP, it might be all internal metabolic effect But if you influence an ion channel through the metabolic effect (i.e. through phosphorylation), the change in MP will develop slowly (slow EPSP, slow IPSP) Change is slow because of it has to go through all the enzyme activity first before influencing the ion channels -Adrenoreceptor  -receptor is a metabolic receptor for Noradrenalin (NA) Binding of NA to  -receptor activates adenylyl cyclase via G-protein alteration adenylyl cyclase  production of cAMP (2nd messenger) cAMP then activates kinases which phosphorylate membrane Ca++ channel This phosphorylation of the Ca++ channel > increase in Ca++ influx (important in heart muscle, increases contractility) Beta-blockers -Adrenoreceptor  -receptor is a metabolic receptor for Noradrenalin (NA) Binding of NA to  -receptor activates adenylyl cyclase via G-protein alteration adenylyl cyclase  production of cAMP (2nd messenger) cAMP then activates kinases which phosphorylate membrane Ca++ channel This phosphorylation of the Ca++ channel > increase in Ca++ influx (important in heart muscle, increases contractility) Beta-blockers Ligands for Metabotropic Receptors ACh: Muscarinic receptor Peptides: substance P,  -endorphin, ADH Catecholamines: noradrenaline, dopamine Serotonin Purines: adenosine, ATP Gases: NO, CO Spread of PSPs PSPs are generated in inexcitable membrane: neuronal dendrites and cell bodies (these areas do not have high density of voltage-gated Na+ channels) Thus, they can NOT initiate an AP Spread of PSPs PSPs are generated in inexcitable membrane: neuronal dendrites and cell bodies (these areas do not have high density of voltage-gated Na+ channels) Thus, they can NOT initiate an AP Spread of PSPs PSPs are generated in inexcitable membrane: neuronal dendrites and cell bodies (these areas do not have high density of voltage-gated Na+ channels) Thus, they can NOT initiate an AP Spread of PSPs Nearest excitable membrane is at the beginning of the axon > trigger zone Spread of PSPs Binding of transmitter > generates PSP PSPs must spread through passive conduction across the membrane to get to the initial segment of the axon Trigger zone PSP Summations Biological tissues have poor cable property (compared to telephone cables) Thus, there will be loss of current (potential) as you go along the membrane before reaching the trigger zone PSP Summations Biological tissues have poor cable property (compared to telephone cables) Thus, there will be loss of current (potential) as you go along the membrane before reaching the trigger zone Types of PSP Summations What are the 2 types of Summation that occur? – Spatial summation: minimum of 10-30 synchronous EPSPs in dendritic tree, each generated at a different synapse – Temporal summation: only a few active synapses, but each generating EPSPs at high frequency; summated potentials reach threshold over a period of time Spatial Summation Spatial summation: Large number of EPSPs in synchrony Spatial Summation Spatial summation: Large number of EPSPs in synchrony Temporal Summation Temporal summation: EPSPs last for about 30-40 ms in duration before dying out, thus, successive inputs on any given synapse generates subsequent EPSPs that add on to pre-existing EPSPs (e.g. 10 ms apart) Summation causing action potential. If two subthreshold potentials arrive at the trigger zone within a short period of time, Stimuli they may sum and initiate an action potential. (X1 & X2) 30 0 Membrane potential (mV) 55 Threshold A2 A1 70 X1 X2 Time (msec) Temporal Summation Temporal summation: EPSPs last for about 30-40 ms in duration before dying out, thus, successive inputs on any given synapse generates subsequent EPSPs that add on to pre-existing EPSPs (e.g. 10 ms apart) Summation causing action potential. If two subthreshold potentials arrive at the trigger zone within a short period of time, Stimuli they may sum and initiate an action potential. (X1 & X2) 30 0 Membrane potential (mV) 55 Threshold A2 A1 70 X1 X2 Time (msec) Inhibitory Post-Synaptic Potential IPSPs tend to be preferentially located on the cell soma, interposed ½ way between the site where EPSP is generated and the trigger zone IPSPs have strategic advantage: due to its location close to the trigger zone > can shunt depolarizing EPSP currents out of cell Inhibitory Post-Synaptic Potential IPSPs located on the cell soma (½ way between the site where EPSP is generated and the trigger zone) can shunt depolarizing EPSP currents out of cell How can IPSPs shunt depolarizing EPSP currents? X IPSP (Cl- Channel) IPSP involves the opening of the Cl- channel The equilibrium potential for Cl- is very close to the resting MP (-70 mV) Therefore at rest, opening of the Cl- channel would result in little change However, when the membrane is depolarized, opening of the Cl- channel will bring the MP back down to -70 mV The net affect of Cl- is basically to ‘clamp’ the MP, which is preventing excitation, thus preventing depolarization > inhibitory effect These IPSPs are very strategically located and they completely block any signal coming from EPSPs simply by positioning right on the soma IPSPs IPSPs in general in the Nervous System, are more important than EPSPs Generating a Spike Train It’s easy to see that when summated EPSPs arrive at the trigger zone, it achieve threshold and an AP (spike) is triggered But what happens when you have a very powerful synaptic input to the post- synaptic neuron persisting in time lasting up to 500 ms? Depolarizing the trigger zone to threshold and sustain that depolarization for 500 ms, you want that powerful input to be translated into continuous stream of APs > This is called the ‘Spike Train’ Generating a Spike Train If we depolarize the membrane above threshold and keep it there, you’ll get one AP and the voltage-gated Na+ channels will inactivate (refractory period) and you can not get another AP until the membrane repolarizes Therefore, after each ‘spike’ we need to get the membrane ‘hyperpolarized’ to restore the Na+ channels to re-open them for the next one We must have Hyperpolarization to generate another AP, otherwise we’ll never generate a ‘Spike Train’ Generating a Spike Train The idea is to overcome the depolarization ‘block’ 500 ms Generating a Spike Train The idea is to overcome the depolarization ‘block’ 500 ms After-Hyperpolarization Voltage-gated K+ channels at trigger zone cause afterhyperpolarizations Hyperpolarization after each spike ensures that Na+ channels reconfigure, and membrane excitability is restored After the hyperpolarization fades away (voltage-gated K+ channels will close when the membrane is repolarized), the MP will be able to shoot right back up where EPSP is taking it and cross the threshold again and a whole new spike and this will repeat until the EPSP fades away Thanks to afterhyperpolarization we could generate a ‘Spike Train' Thank You!