Exam 1 Study Guide Flashcards
Lecture 1 -Weil
- Cell Types in the CNS
Glial cells: Basic function and biology
Oligodendrocytes: Wrap axons in myelin
Ependymal cells: Line ventricles; Produce cerebrospinal fluid
Astrocytes:
- Star shaped
- Structural frame work
- Participate in blood brain barrier
- Regulate what substances from the blood reach neurons
- Survey neurons
- Regulate synaptic communication among neurons
- Have both protective and damaging effects in injury and disease.
Miroglia:
- Similar to Monocytes/macrophages
- Differentiate upon activation
- Long survival (over 6 months)
- Friend of neurons:
- Phagocytose apoptotic neurons
- Secrete neuroprotective factors: BDNF, Neurotrophin 3, etc.
- Resting microglia secrete IL10
- Foe of neurons
- Secrete neurotoxic molecules: *TNF, IL1, glutamate, free radical species, etc.
- Can induce apoptosis
- Interact with astrocytes
Activated vs. resting Microglia
Under normal physiological conditions, microglia in the CNS exist in the ramified or ‘resting’ state. Resting microglial cell are characterized by small cell bodies and thin processes, which send multiple branches and extend in all directions. Similar to astrocytes, every microglial cell has its own territory; there is very little overlap between neighboring territories. The processes of resting microglial cells are constantly moving through its territory; this is a relatively rapid movement, and thus microglial processes represent the fastest moving structures in the brain. At the same time, microglial processes also constantly send out and retract small protrusions, which can grow and shrink. The microglia seem to be scanning through their domains. These processes rest for periods of minutes at sites of synaptic contacts. Focal neuronal damage induces a rapid and concerted movement of many microglial processes towards the site of lesion, and the lesion gets completely surrounded by these processes. This is injury-induced motility. It appears that astrocytes signal to the microglia by releasing ATP (and possibly some other molecules). Microglial processes act as a very sophisticated and fast scanning system. This system can, by virtue of receptors residing in the microglial cell, immediately detect injury and initiate the process of active response, which eventually triggers the full blown microglial activation.
Activation of microglia:
Microglia constantly monitor the environment. Change in pH, osmolarity, extracellular ATP, heat shock proteins, cytokines, chemokines, bacterial components, viral components, cellular debris can cause microglia become activated
When a brain insult is detected by microglial cells, they launch a specific program that results in the gradual transformation of resting, ramified microglia into an ameboid form; this process is generally referred to as ‘microglial activation’ and proceeds through several steps. During the first stage of microglial activation resting microglia retract their processes, which become fewer and much thicker, increase the size of their cell bodies, change the expression of various enzymes and receptors, and begin to produce immune response molecules. Some microglial cells return into a proliferative mode, and microglial numbers around the lesion site start to multiply. Microglial cells become motile, and using amoeboid-like movements they gather around sites of insult. If the damage persists and CNS cells begin to die, microglial cells undergo further transformation and become phagocytes. This is, naturally, a rather sketchy account of the complex and highly coordinated changes which occur in microglial cells; the process of activation is gradual and most likely many sub-states exist on the way from resting to phagocytic microglia. Activated microglial cells may display heterogeneous properties in different pathologies and in different parts of the brain.
The ‘off-signals’ that may indicate deterioration in neural networks are not yet fully characterized. A good example for this type of communication is neurotransmitters. Microglial cells express a variety of the classical neurotransmitter receptors such as receptors for GABA, glutamate, dopamine, noradreanline. In most cases, activation of the receptors counteracts the activation of microglial cells with respect to acquiring a pro-inflammatory phenotype. Maybe the depression of neuronal activity could affect neighboring microglia, turning them into an ‘alerted’ state. In fact, these ‘off-signals’ allow microglia to sense disturbance even if the nature of the damaging factor cannot be identified.
The ‘on-signalling’ is conveyed by a wide array of molecules, either associated with cell damage or with foreign matter invading the brain. In particular, damaged neurons can release high amounts of ATP, cytokines, neuropeptides, and growth factors. Many of these factors can be sensed by microglia and trigger activation. It might be that different molecules can activate various subprogrammes of this routine, regulating therefore the speed and degree of microglial activation. Some of these molecules can carry both ‘off’ and ‘on’ signals: for example low concentrations of ATP may be indicative of normal on-going synaptic activity, whereas high concentrations signal cell damage. Microglia are also capable of sensing disturbances in brain metabolism: for example, accumulation of ammonia, which follows grave metabolic failures (e.g. during hepatic encephalopathy) can activate microglial cells either directly or via intermediates such as NO or ATP.
Glial cells Role in injury
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glial “scar”
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Astrocytes and microglia form “glial scar.”
Ablation of glial scar formation allows axons to grow through site of injury.
Unfortunately it also causes massive loss of neurons.
Cell Types Involved in Inflammation
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monocytes, macrophages, lymphocytes, plasma cells, fibroblasts
Damaging vs. beneficial effects
of Inflammation
In some cases anti-inflammatory treatments are effective, in many cases not.
Inflammation has been implicated in depression,
Alzheimer’s, stroke, TBI, spinal cord injury, Parkinson’s, retinal degeneration, ALS, etc. etc.
Beneficial effects:
Dilution of toxins: produced by bacteria, are carried away.
Entry of Antibodies: Increased vascular permeability allows antibodies to enter the extravascular space, where they may lead either to Iysis of microorganisms, or to their phagocytosis. Antibodies are also important in neutralization of toxins.
Drug Transport: The fluid carries with it therapeutic drugs such as antibiotics to the site where bacteria are multiplying.
Fibrin Formation: Fibrin formation from exuded fibrinogen may impede the movement of micro-organisms, trapping them and facilitating phagocytosis.
Delivery of Oxygen & Nutrients: Delivery of nutrients and oxygen, essential for cells such as neutrophils which have high metabolic activity, is aided by increased fluid flow through the area.
Stimulation of immune response: The drainage of this fluid exudate into the lymphatics allows particulate and soluble antigens to reach the local Iymph nodes where they may stimulate the immune response.
Harmful Effects:
Digestion of Normal Tissues: Enzymes such as collagenases and proteases may digest normal tissues, resulting in their destruction. This may result particularly in vascular damage.
Swelling - The swelling of acutely inflamed tissues may be harmful. Inflammatory swelling is especially serious when it occurs in an enclosed space such as the cranial cavity. Thus, acute meningitis or a cerebral abscess may raise intracranial pressure to the point where blood flow into the brain is impaired.
Inappropriate Inflammatory Response: Sometimes, acute inflammatory responses appear inappropriate, such as those which occur in type I hypersensitivity reactions (e.g. hay fever) where the provoking environmental antigen (e.g. pollen) otherwise poses no threat to the individual. Such allergic inflammatory responses may be life-threatening, for example extrinsic asthma.
Definition of Excitotoxicity
exaggerated and continuous stimulation by a neurotransmitter, especially in those neuronal systems which use glutamate as the transmitter.
Excitotoxicity:
When does it happen?
Cell Death is associated with excessive calcium entry
through NMDA receptors.
Localized increases in [Ca2+]i
trigger physiological events
Excessive Ca2+ loading activates processes that lead to cell death
Neurotoxicity mediated by glutamate receptors is largely calcium dependent
Excitotoxicity:
Calcium
NMDA receptors allows the passage of both Na+ and Ca++ ions. They are more permeable to Ca++
Cell Death is associated with excessive calcium entry
through NMDA receptors
Localized increases in [Ca2+]i
trigger physiological events
Excessive Ca2+ loading activates processes that lead
to cell death
Neurotoxicity mediated by glutamate receptors is largely calcium dependent
Types of glutamate receptors
Ionotropic Glutamate Receptors:
AMPA and Kainate receptors generally allow the passage of
Na+ and K+
NMDA receptors allows the passage of both Na+ and Ca++ ions. More permeable to Ca++
AMPA receptors:
Mediate most fast EPSPs in the CNS
Kainate receptors:
Regulation of neuronal excitability, epilepsy, excitotoxicity, and pain
NMDA receptors mediate most fast EPSPs in the CNS § Anaesthesia § Learning and memory § Developmental plasticity § Epilepsy § Excitotoxicity (eg stroke) § Schizophrenia
Glutamate activates 2 types of ion channels (AMPA and NMDA)
NMDA receptor
A subtype of glutamate receptor; a glutamate-gated ion channel that is permeable to Na+, K+, and Ca2+. Inward ionic current through the
N-methyl-D-aspartate receptor is voltage dependent because of a magnesium block at negative membrane potentials.
The NMDA receptor is distinct in 2 ways:
First, it is both ligand-gated and voltage-dependent.
Second, it requires co-activation by two ligands: glutamate and either D-serine or glycine.
The N-methyl-D-aspartate receptor (aka, the NMDA receptor or NMDAR) is the predominant molecular device for controlling synaptic plasticity and memory function.
The NMDAR is a specific type of ionotropic glutamate receptor. NMDA (N-methyl-D-aspartate) is the name of a selective agonist that binds to NMDA receptors, but not to other glutamate receptors.
NMDA vs. non-NMDA
non-NMDA:
AMPA & KAINATE, both are Ligand-gated ion channels
NMDA (N-methyl-D-aspartate) is the name of a selective agonist that binds to NMDA receptors, but not to other glutamate receptors (ie, not to AMPA or Kainate).
Definition of Oxidative Stress
An excess of free-radicals damages cells and is called oxidative stress.
AMPA receptor
A subtype of glutamate receptor; a glutamate-gated ion channel that is permeable to
Na+ and K+.
kainate receptor
A subtype of glutamate receptor; a glutamate-gated ion channel that is permeable to Na+ and K+.
Why is the brain vulnerable to excitotoxicity?
It contains more fatty acids.
It has few antioxidants.
It has high oxygen consumption.
It has high levels of iron and ascorbate (worse oxidative stress).
Dopamine and glutamine oxidation.
Evidence that schizophrenia is a neurodevelopmental disorder:
Ø MANY RISK FACTOR GENES ARE ASSOCIATED WITH
DEVELOPMENT OF THE NERVOUS SYSTEM
Ø NEURONAL MIGRATION ERRORS IN NEOCORTEX AND
HIPPOCAMPUS
Ø DISRUPTION OF EXCITATORY/INHIBITORY BALANCE
Ø OBSTETRIC COMPLICATIONS AND IMMUNE CHALLENGES DURING PREGNANCY INCREASE RISK
Ø ADOLESCENCE AS A RISK FACTOR FOR SYMPTOM
ONSET
Ø NEURODEVELOPMENTAL ANIMAL MODELS RECREATE
ASPECTS OF THE SCHIZOPHRENIC PHENOTYPE
Positive Symptoms of Schizophrenia
hallucinations; delusions
Negative Symptoms of Schizophrenia
avolition; ambivalent affect
Dysregulation of cholinergic and glutamatergic systems
Antagonists tend to be psychotomimetics
Reduced acetylcholine and glutamate receptors in Schizophrenic patients
Kyenurinine pathway
____ receptor ___ are psychotomimetic
NMDA receptor antagonists are psychotomimetic
There is reduced expression of nAChR and NMDAR mRNA in
patients with Schizophrenia
Reduced acetylcholine and glutamate receptors in Schizophrenia patients
Kynurenine pathway:
Cell Types Involved
Astrocyte, Neurons
Microglia
Kynurenine pathway:
Pharmacological effects of kynurenic acid
Acute elevations of brain KYNA in adults produced SZ-like cognitive deficits (working memory)
Chronic elevations during early development resulted in dysregulations in cortical-subcortical interactions
The mesolimbic modulation of prefrontal glutamate release was markedly weakened;
cortical excitation may be further compromised via loss of dendritic spines
