Chemical anatomy and

Neural plasticity

Topics

• Chemical anatomy
• Synaptic plasticity and the molecular basis for learning

Preparation for class

• Reading: PN6 Chapter 6 (120–143)
• Reading: PN6 Chapter 8
• Watch the Chemical Anatomy video embedded at the end of these notes. It is the second of the two pre-recorded videos (gray backgrounds).

Topic Slide

Alan Hodgkin and Andrew Huxley worked together at Cambridge to understand the nature of neural transmission using the giant axon of the squid as their model system. After their work together was interrupted by WWII, they reunited and published five seminal papers in 1952 that earned them the Nobel Prize in Physiology or Medicine in 1963. You can read more about their collaboration here.

Chemical anatomy

In the lecture on neuronal excitability, I used as examples two neurotransmitters, glutamate and GABA. Both glutamate and GABA are amino acids that open both ionotropic and metabotropic ligand-gated channels (the ligand, in these cases, are the neurotransmitters). Glutamate is a ubiquitous excitatory neurotransmitter within the brain, while GABA is the most common inhibitory neurotransmitter. However, there are more than 100 other neurotransmitters in the brain. Included among these neurotransmitters are several I will consider in more detail below, including dopamine (DA), noradrenaline (NA), serotonin (5-HT), acetylcholine (ACh), and histamine. Acetylcholine and serotonin can act as ligands that open ionotropic channels and can bind with metabotropic channels. However, most other neurotransmitters only bind with metabotropic channels. The biochemical cascades within the cell initiated by metabotropic receptors can result in opening ion channels within the neuronal membrane but can also influence other intracellular functions.

Wired versus Volume transmission

Ionotropic ligand-gated channels open and close quickly. Once the neurotransmitter ligand dissociates from its receptor, the neurotransmitter is rapidly cleared from the synaptic cleft and its action ceases. Ionotropic receptors can operate in the < 5 ms time scale.

Metabotropic receptors, on the other hand, require biochemical pathways within the neuron to be activated before an ion channels opens. The ion channels thus open and close more slowly and can operate over a time scale of hundreds of milliseconds to minutes.

This difference in timing and duration has functional significance. Ionotropic channels are better suited for rapid time-limited transmissions between neurons, while metabotropic are better suited to affect longer duration changes in the post-synaptic membrane. These changes can affect the overall excitability of the neuron for many seconds to minutes. It is easy to imagine, then, how such metabotropic receptors can play a role in arousal, by facilitating or suppressing the likelihood that a neuron will fire over a long time scale.

A distinction is sometimes made between wired and volume transmission. Wired transmission occurs rapidly when a neurotransmitter like glutamate is released by the pre-synaptic membrane and has a rapid effect upon the post-synaptic membranes. Volume transmission occurs when a neurotransmitter is released and diffuses into the extracellular space. It then can affect any receptors it encounters over a wider region than wired transmission. Volume transmission is thought to have more long lasting effects upon the post-synaptic membrane, such as those related to states of arousal. A table describing these different forms of neurotransmission is presented below.

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Chemical systems of the brain

The distinction between wired and volume transmission is important because there are chemical systems within the brain that may operate using volume transmission. These chemical systems originate in small nuclei in the pons, midbrain, and basal forebrain where a relatively small number of neurons have extensive connections across wide regions of the telencephalon. These different systems play modulatory roles in arousal, sleep-wake cycle, emotional response, memory and other processes. We think of these systems as modulating behavior over longer time frames than discrete information processing. For that reason, we refer to the neurotransmitters released by these neurons as neuromodulators.

Receptor types and families

One important fact about neuromodulators and neurotransmitters is that they can bind to different receptors and those receptors can initiate different physiological effects. For example, the very same neurotransmitter or neuromodulator can initiate an excitatory process if it binds to a receptor of one type and an inhibitory process if it binds to a receptor of a different type.

This greatly expands the possible functions of a given neurotransmitter or neuromodulator. It makes it difficult to make generalizations about the function of any particular neuromodulator. This is evinced in the development of drugs that affect particularly neuromodulatory systems. The chemical neuromodulatory systems are often the target of drugs developed to treat psychiatric illness or disorders.

Consistent with the volume transmission concept, increasing or decreasing the release or degradation of neuromodulators have strong persistent effects on behavior. Drugs that activate these systems are called agonists, while drugs that block these systems are called antagonists.

Drugs can work through different mechanisms. For example, an agonist drug might stimulate more synthesis and/or release of a neuromodulator, or it might slow the breakdown of the neuromodulator so that more of the neuromodulator is available in the extracellular space for a longer period of time. It may also directly bind with and stimulate receptors. An antagonist drug can block synthesis or release, or speed its breakdown. An antagonist can also bind with receptors like the neuromodulator itself, but do so with activating the receptor.

If an agonist or antagonist drug has its effect by binding with a receptor, then it is important to know which receptor type the drug binds. Drugs can be constructed that bind selectively to one type of receptor but not to another receptor. In this way, drugs can target specific actions of the neuromodulator related to one receptor type, but not other actions of that same neuromodulator related to a different receptor type.

Affinity

Receptors also differ in their affinity for the neuromodulator or neurotransmitter. Affinity refers to the likelihood of a molecule of a neurotransmitter or neuromodulator binding to the receptor. High affinity receptors have a high likelihood of binding with the molecule, and so can be activitated even when the concentration of the neurotransmitter or neuromodulator is low. Indeed, high affinity receptors can quickly saturate and thus increasing the number of neurotransmitter or neuromodulator molecules will not increase their effect as all of the receptors are already occupied.

Low affinity receptors have the opposite profile. The likelihood a molecule binding to a low affinity receptor is low, and so it takes high concentrations of the neurotransmitter or neuromodulator molecules to increase the likelihood of binding. Thus low affinity receptors are relatively inactive with low concentrations but increase their effectiveness with high concentrations of neurotransmitter or neuromodulator molecules.

Thus, affinity adds yet another dimension to the complexity of neuromodulatory systems.

Major modulatory systems

Here is the image that I used in lecture to discuss four major chemical systems. A fifth system, histamine, will not be discussed further.

Dopamine (DA)

There are two major sources of dopamine in the brain and both are located in the midbrain: the substantia nigra (SN) and the ventral tegmental area (VTA). The SN contains about 135,000 neurons and the VTA contains about 40,000 neurons. These small nuclei target different brain regions with the SN primarily projecting to the dorsal striatum while the VTA projects to the ventral striatum and also more widely in cortical regions.

The SN and VTA have relatively few neurons; however, their axons arborize extensively. Some axons can be 1 meter in length and make 300,000 synaptic connections. Thus, these small nuclei can have a widespread effect upon the brain.

We will discuss the VTA and SN systems in detail later in the semester. Suffice it for now to say that the VTA-DA system is involved in reward and reinforcement learning, while the SN-DA system is more directly involved in motor control. Many drugs strongly influence the VTA-DA system including drugs of abuse such as PCP, amphetamine and cocaine. Antipsychotic drugs also influence the VTA-DA system. The SN-DA system is strongly influenced by drugs such as levo-dopa, which are used in the treatment of Parkinson’s disease.

There are five receptors to which dopmaine binds (D1, D2, … D5). These are often simplified into two families. The D1-like receptor family includes the D1 and D5 receptors. The D2-like receptor family includes the D2, D3, and D4 receptors. The D1-like receptors are generally excitatory while the D2-like receptors generally are generally inhibitory. The D2-like receptors are high affinity and thus activated by low concentrations of dopamine. The D1-like receptors are low affinity, and thus are activated by low concentrations of dopamine.

Noradrenaline (or Norepinephrine)

The noradrenaline (NA) system has as its source a small group of pigmented neurons (which appear blue) in the locus coeruleus (LC) located in the Pons. There are only ~22,000–51,000 pigmented cells in the LC. The NA-LC system is involved in arousal, attention, stress, the sleep-wake cycle among other functions. Some of the drugs that target the LC-NC system are intended to improve attention-deficit disorder. One such drug is Clonidine.

There are three families of noradrenaline receptors: ⍺1, ⍺2, and β, each of which has three receptors for a total of nine adrenergic receptors.

Serotonin (5-HT)

Serotonin is produced by a groups of neurons located in the raphe nuclei of the lower pons. Serotonin plays an important role in regulating mood and emotion, and the many drugs (such as the SSRIs) that target Serotonin are intended to modulate mood and alleviate depression. However, serotonin also plays an important role in motor control. Recall also that 80–90% of the serotonin in the body is used in the enteric nervous system (in the gut).

There are seven types of serotonin (5-HT) receptors numbered 5-HT1 to 5-HT7. These mediate both excitatory and inhibitory effects.

Acetylcholine (ACh)

Acetylcholine (ACh) is widely used in the peripheral nervous system as it the principal neurotransmitter at the neuromuscular junction. However, ACh is also widely distributed in the telencephalon from small clusters of neurons in the nucleus Basilis, the medial septum, and from nuclei within the pons. Acetylcholine plays an important role in alertness, attention, and memory. Many of the drugs aimed at relieving the symptoms of mild cognitive impairment and the early stages of Alzheimer’s disease, such as Aricept, target the ACh system.

There are two major families of acetylcholine receptors: muscarinic and nicotinic. Nicotonic receptors are ionotropic while muscarinic receptors are metabotropic.

We will encounter these chemical systems throughout the course. In particular, we will discuss the DA system in its role in reinforcement learning and reward, the cholinergic system with respect to memory, the noradrenergic system with respect to attention and arousal, and the serotonergic system with respect to sleep.

Neuronal plasticity

Long term potentiation (LTP)

Bliss and Lomo performed a ground breaking study in 1973 showing that an intense stimulus train (a ‘tetanus’) could result in long-lasting increased excitability in neurons in the dentate gyrus of the hippocampus. This phenomenon is called long term potentiation. LPT, and a complementary process known as long term depression (LTD), are forms of neuronal plasticity widely thought to represent fundamental mechanisms for learning and memory. While once thought to be special to the hippocampus (consistent with the latter’s role in memory), LTP and/or LTD has been also been found in the amygdala, the cerebellum, and cerebral cortex, and thus may be a common property of neurons.

Specificity and Associativity of LTP

LTP is pathway specific – it enhances firing at the synapse in which the intense stimulation occurred, not in synapses from other inputs to the neuron that were not simultaneously active.

LTP can be associative – if a weak stimulus and a strong stimulus are simultaneously active, the LTP can enhance both active synapses. This suggests a basic associative learning mechanism.

Mechanisms of LTP

The mechanism of LTP can vary in different neurons.

• Some non-associative LTP is presynaptic and depends upon changes in the release of glutamate by the presynaptic axon. This can mediated by retrograde transmission. Nitric oxide (NO) and cannabinoids are both retrograde transmitters with different presynaptic actions.
• In many cases, however, LTP is post-synaptic and the most well-known form depends upon the NMDA receptor.

How are just the active synapses strengthened? Here are three mechanisms:

• Synaptic tagging: The products of synaptic activity identifies it as being active, so a strengthening signal can limit itself to only active synapses.
• Retrograde transmission: A post-synaptic region can alter the pre-synaptic region to release more transmitter.
• Neural back propagation: The depolarization at the axon hillock sufficient to open sodium voltage-gated channels and trigger and action potential causes a passive wave of depolarization that sweeps backwards and further depolarizes active dendritic processes. This ‘reinforces’ all active synapses by opening NMDA receptors. This process is of great interest to computational neuroscientists as it resembles a ‘teaching signal’.
  • There is evidence that back-propagation may include active signaling and not just passive wave.

Most investigators recognize two phases to long-term potentiation:

• Early LTP occurs quickly (4–6 hours) and does not depend upon gene transcription.
• Late LTP occurs more slowly (> 6 hours) and depends upon gene transcription and protein synthesis.

The NMDA glutamate receptor

There are different types of glutamate receptors:

• ionotropic
  • AMPA receptor, or AMPAR
    • AMPA receptors can be phosphorylated, after which they increase their conductances
  • Kainate
• metabotropic (mGlu)
  • mGlu receptors are G-protein coupled
  • there are 3 groups of mGlu receptors which differ in their intracellular signaling mechanisms
  • mGlu receptors play an important role in non-NMDA mediated LTD
• NMDA
  • NMDA receptors are both ligand-gated AND voltage gated
  • NMDA receptors are activated by glutamate, but their channels are blocked by Mg++.
  • The Mg++ is displaced when the surrounding membrane is depolarized to a particular threshold, at which point the channel is open.
  • Once unblocked, the NMDA channel admits both Na+ and Ca++.

Calcium signaling

Calcium is a ‘second messenger’ in that its entrance into the neuron initiates different biochemical cascades within the cell. You can read about Ca++ pathways here):

• Ca++ ions enter through NMDA receptors
• Ca++ bind to calmodulin
• Calcium-calmodulin-dependent kinase II (CaMKII) is activated
  • CaMKII phosphorylates AMPA receptors making them more sensitive to glutamate
  • CaMKII also increases the number of AMPA receptors at the synapse. This is a process called receptor trafficking, whereby additional AMPA receptors that are stored inactively within the dendrite merge with the neuronal membrane at the synapse and become active. This can strengthen the response of the synapse to further stimulation.

Note that a different Ca++ pathway is responsible for long term depression. In LTD, the number of AMPA receptors in the synapse decrease and the synapse is thus weakened.

Structural changes in neuron associated with LTP and LDP

Structural changes to the neuron can occur as a consequence of the Ca++ entry. For example, new dendritic spines may be created, and thus the neuron becomes more sensitive to particular input. This is experience-dependent plasticity.

• Increased gene expression (i.e., protein synthesis — perhaps of AMPA receptors) also occurs during the development of LTP.
• Enlargement of the synaptic connections and perhaps the formation of additional synapses occur during the formation of LTP.

LTP and LTD is associated with growth and retraction of dendritic spines:

• I showed examples of spine growth and retraction
• I discussed recent study that showed transient changes in spines in hippocampus that lasted as long as memories in an animal model. However, cortical spines were more long-lasting. Supports concept that hippocampus is needed for consolidation, but not after memories have been stabilized in cortex.

The retraction and extension of spines can change the volume of the hippocampus. Keep this in mind for future lectures.

Is LTP functional?

• Yes, I provided an example where blocking the NMDA receptor with a drug caused a rat to NOT learn a water maze task.

Videos

Prerecorded lectures for Fall, 2020

Neuronal plasticity is discussed in Part 1 below (1:00:57):
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Chemical anatomy is discussed in Part 2 below (15:47):
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Previously recorded ‘live’ lectures from past iterations of class.

The video below is from a lecture on this topic in Fall 2018.

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The video below is concerned with neuronal plasticity, long-term potentiation, and long-term depression. It was recorded in Fall 2019.

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