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Anna’s NeuroNotes

Mcb80x
The junctions between neurons are called SYNAPSES

● there are both electrical and chemical synapses

dendrites receive signals - from greek word dendron, "tree"

● electrical synapses less common in our own nervous system

Basics of synapse transmission

● simplest way is by having two neurons CONNECTED to one another (electrical synapse)
○ physical pore that allows ions to flow through
○ intercellular current - causes propagation of action potential through the
downstream neuron
○ very fast- used in simple circuits like escape reflexes
○ also allows for bi-directional signaling

Chemical synapses

● rely on release of chemical substances through a space btwn the neurons called the
synaptic cleft
○ cleft abt 20-40 nm in size (thousand of diameter of a human hair)
○ small bc signaling molecules have to cross this gap vis diffusion
■ chem signal released by presynaptic cell (goes to postsynaptic)
○ slower than electrical synapses

advantages of chemical signals over electrical: (esp mamalian)

● diversity!
○ electrical synapses only use voltage

neurotransmitters:

● chemicals that tell the postsynaptic neuron to increase or decrease their likelihood of
firing
○ other chemicals such a dopamine, serotonin, or epinephrine (adrenaline), can
have more complicated and longer term effects on neural circuits
■ known as NUEROMODULATORS

Chemical signals enforce directionality

 ● released from one side of synapse and are received by the post synaptic neuron
○ ensures the flow of a signal in one direction

● chem signal also does not guarantee that a spike (action potential) will actually occur in
the p.s. cell
○ not uncommon for downstream neurons to require multiple spikes from different
sources to reach threshold where that cell will transmit an action potential itself
■ summation of signals = computational neuronal circuit

typical neuron has three main parts:

1. A dendritic arbor (or "tree")

2. The cell body
3. An axon

But there are some exceptions:

● neurons without axons

○ both receive and send information through their dendrites
■ ex: granule cells, interneurons found in the olfactory bulb and in the
hippocampus, can send either activating or inhibitory signals through their
dendrites (depending on their location)

Important to remember:

DIFFUSION is how chemical signals travel in nervous system

Anatomy of the Synapse

● synaptic space is a tightly organized place whose geometric is strictly regulated by diff
adhesion molecules
○ tons of molecular machinery regulating its chemical makeup
● axon balloons outward slightly as it approaches synapse - called presynaptic terminal
● neurotransmitters or neuromodulators are the chemical signals sent through the synapse
○ these molecules are packaged inside of the presynaptic axon into vesicles
(containers almost, made of cell membrane materials)
● arriving action potential forces vesicles to fuse with cell membrane, releasing its contents
into the synaptic cleft
○ then diffuse across cleft and bind to molecules called receptors on other side of
cleft (postsynaptic neuron now)
● receptors have a job of binding to a very specific molecule or class of molecules
 ● diff receptors send diff signals

receptor examples:

● some are ion channels (they open when binded to the neurotransmitter of interest)
○ Called IONOTROPIC RECEPTOR RECEPTORS
● some receptors set of a chain of complex reactions (molecular cascades within cell)
○ called METABOTROPIC RECEPTORS
○ can even alter gene expression within the cell

The Presynaptic terminal

NMJ = neuromuscular junction (where nerves connect to muscles)

● primary neurotransmitter here is acetylcholine (used for voluntary motor control)

○ big role in anesthesia - muscle relaxants like succinylcholine and its derivatives
used for this
● postsynaptic potential = response of the postsynaptic neuron, which can be classified
into:
○ excitatory, neuron likely to fire bc its closer to threshold (EPSP's)
○ inhibitory, where the signal makes the neuron less likely to fire (IPSP's)

at NMJ, things are a little different

● nerves touching muscles fibers form flat structures called end plates
○ potentials here are called end plate potentials (EPP's)
● synaptic activity is proved by blips in between potentials that happen in the absence of
any stimulus (Katz)

Presynaptic Terminal cntd

● blips in membrane potential could only be recorded when probe placed in postsynaptic
terminal..
○ came from cell itself
● by adding drugs (neostigmine, curare) these blips can be blocked or enhanced!
● curare is a paralytic agent
○ EPP's would disappear altogether
● and neostigmine destroys enzyme that destroys acetylcholine, giving a single dose of
AC a stronger effect
○ EPP's increase in amplitude and duration

more..

● what happens to EPP's happens to the blips as well! (blips are tiny voltage signals from
neural activity)
○ blips look like smaller (minis) EPP's
 ● even when presynaptic terminal hasn't been stimulated, there's still a small probability itll
release molecules into synaptic cleft
● minis are these random releases
● minis are roughly same amplitude

What happens when you manipulate the concentrations of ions OUTSIDE the cell?

● theres a precise dependence btwn EPP amplitude and concentration and timing of
calcium in the NMJ (Ca+ plays some role in determining EPP amp)
○ also timing. if calcium came have presynaptic nerve was stimulated, no EPP
○ needs to be extracellularly present when pre syn action potential arrived
■ otherwise no effect
● if you inject calcium directly into the presynaptic terminal (inside the cell) without
electrically stimulating the cell, you will still see and EPP
● concentration of intracellular calcium is tightly controlled by the cell (v important signaling
ion)

big idea tbh from Katz:

● instead of being released individually, transmitter molecules are released together in

packages of approximately fixed number
● rather than continuously flowing out of pre syn neuron, neurotransmitters are released in
discrete quanta (groups)
○ found out bc the normal signals are in multiples of the voltage of the minis
● VESICLES are what transport N.T.'s (neurotransmitters)

to summarize calcium importance:

1. action potential arrives at presynaptic terminal

2. triggers opening of voltage gated and calcium channels (intracellular [ca+] increases)
3. more Ca+ increases probability of neurotransmitter vesicle being released

Visualizing the synapse

● remember light vs electron microscopy (talked abt in bio this year!!)

○ light m's don't have enough resolution to study these tiny structures
● electron m revealed presence of hundreds of small circular structures in the presynaptic
terminal
○ after heavy stimulation of that neuron, the pre syn terminal found with far less of
these structures!
● e microscopes confirmed and expanded upon our info about synapses!
○ there are two diff types of vesicles: ones that were docked and ready to go right
behind
○ pre syn membrane, and another pool further back waiting to be loaded and
docked
● e microscopes also being used to visualize brain circuitry at a high resolution
SNAREs
how does calcium cause the fusion of vesicles to the presynaptic membrane?

● SNAREs = proteins @ surface of the vesicle and the presynaptic membrane

○ synapse associated proteins that have similar structure and function across many
largely different organisms
■ this suggests their evolutionary importance
● all major synaptic vesicle SNARE proteins have been identified

Functions include things like:

● vesicle fusion (fusing with membrane to release neurotransmitters) in a synapse is

catalyzed by the interaction of a vesicle associated SNARE protein (V-SNARE) with
other SNARE proteins on the membrane, called target SNAREs (T-SNARE)
○ synaptobrevin main V SNARE, SANRE 25 and syntaxin main T SNARE
● other proteins bring the v and T snares together
● V snares are what are found on surface of vesicles (vesicle membrane really) while
T-SNARES found in membrane of pre syn terminal

calcium's role:

● regulates interactions btwn proteins on vesicle and pre syn membrane

○ remember, when cell depolarizes, voltage gated Ca+ channels open and ca+
flows inside cell
● synaptotagmin binds to calcium and speeds vesicle release
○ this is what allows neurotransmitters to flow into the synaptic cleft

interesting:

● 2 toxins (botulinum. main botox ingredients, and tetanus) are enzymes that target snare
proteins and inactivate them
○ ultimately inhibit release of acetylcholine (neuro trans that causes muscle
contraction)

Synaptic vesicles contain similar amounts of neurotransmitter molecules between them and
have specialized machinery on their surface that allows rapid docking and fusion, but don't need
to be remade by the neuron after each stimulation ( because vesicles are recycled)
golgi method, or black neuron staining, in the late 1800s allowed for singular neurons with their
branches to be viewed under microscopes

Big Important Ideas:

 ● fast excitatory postsynaptic potentials are mediated primarily by
cation-selective ion channels, while fast inhibitory postsynaptic
potentials are mediated primarily by anion-selective ion channels
● PNS = primary excitatory receptors are nicotinic acetylcholine
receptors, which conduct both sodium and potassium, while the primary
inhibitory receptors are chloride-conducting glycine receptors
● CNS = primary excitatory receptors are the NMDA and AMPA glutamate
receptors, which both are promiscuous to calcium, sodium and
potassium. The main inhibitory receptors in the brain are the
chloride-conducting GABA receptors.

● once a neurotransmitter is released, it traverses the synaptic cleft in one microsecond

(one millionth)
● neuro transmitters travel at about 0.05 mph
○ [this is a very quick process given the small distance it crosses]

Life of a Neurotransmitter

● once released, has one of five fates

1. travel across synaptic cleft (20-40 nm wide) and bind to its dedicated receptor
○ if allowed 2 remain in synaptic cleft 4 too long, could bind and unbind to
dedicated receptor and could activate postsynaptic cell multiple times
■ time would be lost
○ this exposes necessity for mechanisms to shut off neurotransmitter action in syn
cleft before diffusing away

These mechanisms are:

● as it bind to its receptor, the neuro trans and even post syn receptor protein can be
absorbed into post syn cell
● neuro trans can be broken down by enzymes in syn clef
○ acetylcholine cleaved by acetylcholinesterase
● can be taken up by transport proteins on surface of surrounding glial cells surrounding
and even sometimes invading the syn clef
○ combos of all these examples are also possible
● acetylcholine, after being broken down, can later be recycled too

Types of Synapses (EPSPs and IPSPs)

● fast vs slow synapses

○ milliseconds vs hundreds to thousands of times slower
 ● strong vs weak
○ related to threshold of post syn neuron to be able to fire an action potential
● excitatory vs inhibitory
○ defined by direction of effect of incoming signal on post syn membrane

*a neuron type is defined by the transmitter that is released*

● excitatory (EPSP) neuron transferring signal promotes firing of downstream neuron

note: its the voltage at the axon hillock (where soma joins axon) that ultimately decides whether
an action potential is fired or not

● so effect of EPSP diff at post syn membrane than at axon hillock bc of:
○ shape of dendritic arbor
○ # of inhibitory and excitatory synapses
○ timing of inputs (just naming a few)^
● generally a single EPSP won't reach threshold for an action potential in the post
syn neuron
○ could be multiple successive signals from a single neuron or signals from
diff neurons

THIS IS WHY SINGAL PROCESSING IN THE BRAIN IS SO COMPLEX

● also IPSP, which reduces likelihood of post syn firing an action potential
○ when inhib neuron sends signal to post syn neuron, post syn membrane
stays toward resting potential (instead of getting depolarized like from
EPSP)
● like a stop signal.. subtly changes electrical properties of membrane to work
against EPSPs
● diff neurons associated w different Nernst potentials
● if we open up channels for a specific ion, then the membrane potential moves
toward that ion's nernst potential
○ neuron tends to fire when mem potential is more positive
● for example: an IPSP caused by opening chloride channels into membrane
○ when we artificially make membrane potential more positive, we can start
to see the IPSP effect

how does it work?

● at rest, like an anchor, making it harder to pull potential to firing threshold

diff forms of inhibition in nervous system:

 ● opening potassium
● closing calcium
● some inhibitory synapses are on dendrites (subtract away certain inputs)
● others on CELL BODY of neuron (act as cell-wide drag) aka somatic
○ different places, different behaviors
● fast EPSPs are usually mediated by sodium ionotropic channels

EPSP's in Depth
Acetylcholine, released @ NMJ, is the first neurotransmitter ever discovered!

● interact w nicotinic receptors on motor end plate (NMJ equivalent of post syn membrane)
● FAST and STRONG

nicotinic acetylcholine receptors

● can also be opened by nicotine.. (stimulant)

● results in muscle contraction
● high degree of spacial specificity is crucial to success of EPSP strong and fast synapse

how?

● nic. acet. receptor = ligand-gated ion channel

○ open when a specific chemical (a ligand) binds to it
● structure so that small ions can pass through
● when the ligand binds, its structure changes, allowing the flow of ions through its central
pore
○ but only when both binding sites on receptor are filled
● TONS of receptors are needed for muscle contraction

diff btwn brain currents and electrical currents in a circuit:

● In a piece of wire, current results from the movement of negatively charged particles
called electrons, while in neurons, the movement of ions generates membrane currents.

Acetylcholine Receptors in Depth

● which ions flow through them?

○ "promiscuous" cation channel - allows sodium, potassium, and small amt of
calcium
● extracell [Na+] > intracell [Na+]
● extracell [K+] < intracell [K+]
● sodium flows into cell via channel and depolarizes it, generating an outward current
● potassium flows out generating inward current
○ continues until theres no net charge transfer btwn in and outside
● inward current are EQUAL and OPPOSITE to outward currents
 ○ this "reversal potential" is the average of the sum of sodium and potassium's
nernst potentials
■ like nernst stored equilibrium
● desensitization - if two many signals occurring (being reused) individual channels close
○ of acetyl, good for muscle relaxant during surgery
● there pesticides, plant poisons, and man made compounds that can also lead to
desensitization (which can cause paralysis, etc)

there is an inward current when either

1. Positive ions move into the neuron

2. Negative ions move out of the neuron

inward currents, by convention, are negative.

positive currents are just the opposite of this
Excitation Disease States

● More than half of the currently known genetic mutations associated with congenital
myasthenic syndrome are found in one of the four genes encoding the acetylcholine
receptor subunits
● Myasthenia gravis is an autoimmune neuromuscular disease caused by
blockade/destruction of acetylcholine receptors at the postsynaptic neuromuscular
junction

Glutamate and Glutamate Receptors

● glutamate is a neurotransmitter in the brain (prominent role in CNS)

○ responsible for most fast EPSPs
● naturally occurring amino acid and building block of many proteins (aside from neuro
trans)

released by glutamatergic neurons

● diversity of function comes from diversity of types of glutamate receivers

● 2 groups:
○ ionotropic receptors = ion channels which directly let ions pass
■ faster than metabotropic
○ metabotropic receptors = change metabolic and biochemical pathways indirectly
■ use G protein coupled receptors (GPCRs), which aren't ions
■ instead of letting ions pass directly through a core, they sense molecules
outside the cell and in response activate certain signal transduction
pathways, leading to diff cellular responses inside the cell
○ GPCR's are 4-5% of known human protein coding genome!!
○ target of 40% of all modern medicinal drugs
AMPA and NMDA Receptors

● glutamate can interact with a wide range of both ionotropic and metabotropic receptors
in the CNS
● main two groups of ionotropic receptors in CNS are AMPA and NMDA receptors

AMPA

● mediate fast EPSPs

● most commonly found receptor in nervous system and common in diff parts of the brain
● central AMPA receptors are promiscuous ion channel permeable 2 all cations
● exclusively ligand gated

NMDA

● most studied for their role in synaptic plasticity and learning and memory function
● can be activated both by a ligand and by changes in membrane potential!
● activation results in opening of central pre which is non selective to cations
○ (lets in calcium, sodium, potassium, etc) w/ potential close to 0
● often called "coincidence detectors"
● normally has a magnesium ion blocking its central pore... so needs depolarization for
magnesium to exit this central receptor area
○ this depolarization is typically caused by an AMPA receptor opening
● they get activated not only when there is glutamate released into the cleft (a presynaptic
event), but also when AMPA receptors start getting activated (a postsynaptic event)

cool lab stuff:

● The young brain has NMDA receptors only

● As expected, the adult brain has both NMDA and AMPA receptors

IPSPs in Depth

● in CNS, most IPSPs due to action of ligand gated channel like GABA and glycine
receptors

GABA

● primary IPSP generating receptors in brain

Glycine receptors

● bind to natty occurring amino acid glycine are primary IPSP generating receptors in the
spinal chord
● both structurally similar to acetyl nicotine channel, but instead of being lined w negative
charge to let cations pass, they are lined w neutral or positively charged amino acids
 ● both called anion-selective ion channels, caused increase in chloride conductance
● more Cl- force post syn neuron to stay close to equilibrium potential of chloride (-65 mV,
close to -70mV resting potential)
● can be used to stop AND block signals

example:

● strychnine, (common in rat poison), powerful antagonist of glycine receptor

○ causes muscular convulsion due to LOSS of inhibitory action, and can lead to
death via asphyxiation
● Barbiturates are drugs that act as CNA depressants by acting as GABA receptors in the
brain
● benzodiazepines have replaced this drug now (think valium and xanax)
○ less dangerous to overdose on
● used for things like anxiety and insomnia
● sedative, sleep inducing, anti anxiety, etc

ALCOHOL

● also known to modulate ionotropic GABA receptors (but mechanism poorly understood)

positive allosteric modulation:

● occurs when barbiturates in the central nervous system make GABA receptors more
likely to get activated by binding outside the normal ligand-binding site on the receptor.

Inhibition Disease States

● an example of one such neurological disorder is hyperekplexia, characterized by an

exaggerated startle response to olfactory or touch stimuli
○ symptoms:
■ generalized stiffness
■ excessive startle response starting at birth (brief stiff period following
startledness)
■ forces closure of eyes and extension of extremities, sometimes
uncontrollable falling
● Caused by genes that code for post and pre syn proteins involved in glycine neuro trans
pathway (including glycine receptor)
○ symptoms vary based on the gene that is mutated
● single mutations in glycine receptor impair its ability to open up when activated
○ this reduces chloride influx
○ IPSP function is lost in glycine transmission
● most common treatment actually increased IPSP effects of GABA
Main Ideas from this chapter:

Information Processing

● there are sensory, motor, central, and peripheral circuits

● groups of interconnected neurons are sometimes called circuits
● distinct regions of a neuron (along dendrites, soma, and initial axon segment) are
specialized for either receiving excitatory or inhibitory input (but rarely both)
○ excitatory input thought 2 mainly occur on dendritic spines
 ○ inhibitory input thought to mainly occur on dendritic shafts, cell body, and on axon
initial segment
● single neuron can receive signals from thousands of E and I synapses

How do these inputs combine??

● each neuron has to filter and integrate lots of signals and decide whether it was send an
action potential
● this is decided to be due to 5 key factors (the next 5 sections)

Synaptic Efficacy and Distance

● As an EPSP travels down the dendrite, its amplitude gets smaller

○ off note: soma size also influences the response amplitude (apparently)

the length constant tells us the distance a signal needs to travel before reaching 37% of its og
level
lambda = sqrt(R membrane / R axial) in ohms * cm and in ohms/cm

● the more length constants away a signal has to travel, the more the signal decreases
● axial resistance = tendency of cell's cytoplasm to oppose the current flow
○ if this goes up, then less current will make it to the cell body
● membrane resistance = how hard it is for current to travel across the membrane
○ ex: via passage leakage ion channels
○ if this is low, more current flows out of dendrite before it gets into cell body
● bc the first EPSP was closer, it traversed fewer length constants and was therefore
stronger at the cell body

another reason why signals from a more distant branch would be much smaller

● due to shape of neuron

○ the further from the cell body, the smaller and thinner neuronal projections tend to
be (like tree branches)
■ thinner processes have higher axial resistance
● farther away and EPSP is from axon initial segment, the less influence it has on deciding
whether an action potential will fire

Synaptic Summation

● their is a NON-LINEAR summation os EPSPs when more than one are fired at once
○ combined EPSP tends to be larger than the sum of the two
● this is due to:
○ Driving force
■ DVi=Em-Ei
■ where Em is the membrane potential and Ei is the Nernst potential of ion i.
 ○ Dendritic action potentials
■ (is past decade) voltage-gated channels and even action potentials in
dendrites have been observed, so there's a whole host of complicated
potential nonlinearities in dendritic summation
○ Action potential backpropogation
■ Action potentials don't just stay in the soma
■ The same cytoplasm that conducts dendritic postsynaptic
potentials to the soma also passively conducts currents from the
action potential back into the dendritic arbor
■ These back propagating action potentials influence the effects of
incoming EPSPs

Synaptic Inhibition

● opening of inhibitory channel hold membrane at abt resting potential (Cl- is -65mV)
○ effectively cancels out IPSP
○ this effect is called "shunting"
○ another example of non-linear summation!
● for inhib neuron to pay optimal role in controlling action potential, its synapse must be
located between the excitatory synapse and the post syn soma (otherwise EPSP will still
make it to soma and depolarizes the neuron)
● a single IPSP from a synapse on the soma can cancel out EPSPs arriving from
anywhere in dendritic arbor
○ however, and IPSP on the dendritic branch would tend to only shunt EPSPs
upstream of its own location on the dendritic arbor

Synaptic Temporal Summation

excitation / inhibition balance is required for normal brain function

● when an EPSP fires multiple times in succession, this results in a HUGE depolarization
of the post syn membrane
● The EPSP recorded in neuron A after firing twice in close succession is larger (additive)
in amplitude and different in shape compared to the EPSP after a single activation
○ however, this summation is nonlinear given how insanely large the 4x amplitude
is

Ways to describe temporal summation

● The fast rise and slow fall of the EPSP caused by the state of 'openness' of a neuron's
ligand-gated ion channels.
● The second EPSP piggybacking onto the falling phase of a previous EPSP when the
neuron is still depolarized

Synaptic Temporal Inhibition

● IPSOs have complex effects on shape, amplitude, and success on EPSPs

 ○ Can cancel out temporal summation, etc

Convergence and Divergence

● convergence = when multiple (possibly) different inputs come together to synapse on a

single downstream neuron
○ pervasive thru-ought NS and essential 2 survival
○ intuitive; brains must bring together info collected from all of our senses and
synthesize them into a coherent whole!
○ brains = masters of convergence
■ ex: inputs collectively converging to trigger fear threshold
● divergence = one neuron sends a signal to many other neurons
○ see something dangerous, signals must be sent to the entire body (whole body
alerted in some way)
■ ex: heart rate rises, breathing hastens, pupils dilate, muscles tense

simple examples of pure convergence and divergence

● stretch (myotatic or tap) reflex

○ monosynaptic reflex with automatic regulation of the skeletal muscle length
○ each spindle in skeletal muscle sends signal to spinal chord (axons stretch into it)
where they converge onto a motor neuron
○ motor signals from one motor neuron diverge so that all muscle fibers contract

Central Pattern Generators

● Recurrence = where some chain of connected neurons eventually loops back onto itself
○ aka FEEDBACK
● just two neurons in the simplest case..
○ often way more complex, resulting in subtle interdependencies in neuronal
circuits
● "CPG" or Central Pattern Generator relies on recurrence
○ neuronal networks that can produce rhythmic patterned outputs, even in the
absence of ongoing stimuli
■ for example, contractions of our digestive tract (peristalsis)
■ can be combination of excitatory and inhibitory neurons
○ basic pattern of neuronal activity needed to drive walking can be produced by
spinal chord alone!
■ simpler than it may seem
■ no processing from brain needed

How?

● some kinds of neurons contain mechanisms that allow them to fire rhythmically even in
isolation
 ○ common feature of CPGs is a recurrent connectivity pattern causing 2+
populations of neurons to fire in a rhythmic way out of phase
○ when A fires, B will fire later
○ when B fires, it in turn activates A later
■ activity ping pongs btwn these two
● external inputs can also modulate the activity of a CPG
○ could slow it down/speed it up or command it to stop or start

divergence, convergence, and recurrence together can produce an array of complex behaviors,
even in circuits without lots of neurons