Thursday Apr 26

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• Thursday Apr 26
• Review sessions
• Thursdays 130 200
• May 3 and may 10
• McC 4th flr Rm 272

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• 3. Mixed actions Black Widow
  Spider Toxin
• Only female venom is dangerous to humans
• First causes excessive release of Acetylcholine,
  then causes vesicles to clump together, clog up
  presynaptic membrane, and prevent further release
• Paralysis and death

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• Diseases Relevant to Cholinergic System
• Myasthenia Gravis
• Neuromuscular disease characterized by severe
  weakness and fatigability of muscles
• Loss of nicotinic cholinergic receptors on
  surface of muscle produces inability to maintain
  muscle activity for more than a brief period
• Enough Ach, not enough receptors (receptor
  content reduced by 60 in most common form of MG)
• autoimmune reaction where antibodies are built
  against bodys own nicotinic receptors
• May be caused by a virus (possibly transmitted by
  birds), genetic vulnerability
• Treated by anticholinesterase drugs (neostigmine
  pyridostigmine) that help provide more Ach to
  stimulate the limited receptors
• Immunosuppressive drugs (prednisone,
  cyclosporine, and azathioprine) may also be used.
  
• May remove thymus gland

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• Relevant Diseases
• 2. Alzheimers Disease
• Neurocognitive disorder marked by significant
  memory loss
• More common in elderly
• Deficiency of function of cholinergic neurons
  originating in the basal forebrain and sending
  their axons to cortex, hippocampus, and olfactory
  areas
• Buildup of beta amyloid protein causes tangles in
  axons (neurofibrillary tangles) that lead to
  dysfunction then degeneration of axon terminals

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• Drugs used to Treat Alzheimers Disease
• (Excess dietary choline does not appear to help)
• Long acting anticholinesterase drugs used to take
  advantage of what little Ach can be released
• For mild to moderate AD
• tacrine (Cognex) - 1993
• donepezil hydrochloride (Aricept) 1996
• rivastigmine (Exelon) 2000
• galantamine hydrobromide (RazadyneTM-formerly
  called Reminyl) - 2001.
• Help slow the worsening of symptoms long term
  efficacy not good
• For treatment of moderate to severe AD
• donepezil hydrochloride (Aricept) 2006 -
  approved for severe AD

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Drugs used to Treat Alzheimers Disease 2. Drugs
that focus on Glutamate mechanisms of
excitotoxicity idea is that excititoxicity may
be killing the Acetylcholine neurons Memantine
(Namenda) 2003 - NMDA (N-methyl-D-aspartate)
receptor antagonist - helps restore the function
of damaged nerve cells and reduce abnormal
excitatory signals 3. general stimulant drugs
that may help improve memory in early stages of
AD nicotine modafinil (Provigil) 4. Drugs
on the horizon focus on facilitating memory
formation through Glutamate mechanisms ampakines
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• Glutamate
• A. General functions in brain
  (non-neurotransmitter functions) physiological
  actions within neurons
• - important metabolic role
• - detoxifies ammonia in brain
• - building block in synthesis of proteins and
  peptides
• - precursor for GABA

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B. Synthesis and metabolism when
neurotransmitter - made in axon terminals from
glucose (coming from cell metabolism) and from
glutamine (coming from glial cells) -
glutaminase is the enzyme that converts above to
glutamate (Glutamic acid) - stored in vesicles
and released by Calciumdependent exocytosis -
action terminated by high affinity reuptake
transporter on presynaptic neuron and glial cells
- the reuptake transporters also help to
maintain extracellular GLU below levels that may
damage neurons - extracellular enzymes not
relevant to termination of action
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C. Receptors 5 types responsible for most
excitatory transmission in the CNS 1. NMDA
receptors high threshold ionotropic excitatory
longterm potentiation and memory formation,
developmental plasticity, epilepsy, neurotoxicity
related to brain damage 2. AMPA receptors -
ionotropic, excitatory LTP and memory
formation 3. Kainate receptors - ionotropic,
excitatory 4. AP4 receptors (inhibitory
autoreceptor) 5. ACPD receptors slow, second
messenger action that modifies inositol phosphate
metabolism Individual synapses that use GLU
appear to use combinations of these receptors,
rather than a distinct type.
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D. The NMDA-AMPA receptor complex Found
throughout brain and spinal cord, particularly
dense in hippocampus and cerebral cortex Role in
longterm potentiation and memory formation,
developmental plasticity
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The NMDA-AMPA complex has several distinct
binding sites each can modulate the activity of
the overall receptor and the opening of Na and Ca
channels Sites responsive to GLU, glycine,
phencyclidine (PCP) and ketamine, polyamine site
activated by certain excitotoxic agents
(antagonists here can be neuroprotective). Glycin
e site is inhibitory dramatically alters
NMDA-receptor mediated responses important to
epilepsy and excitotoxicity. Drug dev for agents
to treat epilepsy and prevent ischemic brain
damage. D-serine is also an endogenous ligand
for the glycine site it is produced in glia ( a
gliotransmitter) and is an example of the impt
role glia play in synaptic transmission
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LTP Structural changes in the brain that are
associated with learning and memory (and the LTP
process) 1. Gross changes 1st known Enrichment
studies by Rosenzweig (1960s) Greenough (1970s -
current) Rats raised in enriched vs impoverished
environment -- different brain
characteristics Enriched heavier
brains thicker cortex more capillaries more
proteins more glial cells larger synaptic
fields
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2. Underlying mechanisms now known - Changes in
neurons, glial cells, and circuitry occur through
the process of Long Term Potentiation History 1.
Hebbs Rule (1949) - hypothesized that the
cellular basis of learning involves strengthening
of a synapse that is repeatedly active when the
postsynaptic neuron fires neurons that fire
together, wire together 2. Environmental
Enrichment Studies understanding of gross
changes 3. Elegant cellular and molecular studies
of LTP
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Long Term Potentiation - long term increase in
the excitability of a neuron to a particular
synaptic input resulting from repeated high
frequency activity of that input Repeated
activation appears to reduce the threshold for
firing at that connection point
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Neurons throughout brain show changes with
experience. LTP mechanism appears to be active in
many different brain areas - hippocampus,
amygdala, visual cortex, frontal cortex
specifics vary How LTP works is best understood
for the hippocampus - a model for understanding
other areas In hippocampus, Glutamate is critical.
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• Long Term Potentiation in the Hippocampus
• certain neurons in the hippocampus use glutamate
  as the neurotransmitter
• many different postsynaptic receptors for
  glutamate
• AMPA and NMDA receptors play the best understood
  roles

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Glutamate is released into a synapse when a
neuron fires. GLU then binds with receptors. AMPA
receptor binding produces EPSPs (excitatory
postsynaptic potentials remember these?) But
the binding of Glutamate at NMDA receptors does
not open channels easily to cause EPSPs
channels are blocked by Magnesium ions
(Mg) -------------------------------------------
---------------------- When these synapses
repeatedly receive GLU from presynaptic neuron
firings, the EPSPs caused by the binding at AMPA
receptors then cause the Mg block on the NMDA
channels to be removed. Then NMDA receptor
channels open and allow Ca in and the
postsynaptic neuron fires NMDA receptor bindings
and Ca influx are important for establishment
of LTP.
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Synaptic activity occurs repeatedly. Each time,
the GLU binds with AMPA and NMDA receptors. After
AMPA receptors have been repeatedly stimulated by
GLU binding, things change in the NMDA receptor
response. The Mg block is removed allowing
EPSPs to result from NMDA binding. When the
neuron fires due to NMDA receptor activity and
consequent elevation in Ca, then LTP
occurs. The next time the same circuit (sets of
synapses on the neuron) send messages again, the
neuron will fire more easily. This is long term
potentiation. If Ca levels remain elevated for
a sufficient period of time, LTP then lasts for
days or more.
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• Manipulations
• Prevent NMDA activity - LTP does not occur.
• Limit expression of genes that produce NMDA
  receptors, limits learning in mice.
• Increase expression of genes that produce NMDA
  receptors, mice learn better. (the Doogie mouse)
• prevent rise in postsynaptic Ca - no LTP
• mimic rise in Ca - LTP occurs

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• How does the circuit become easier to activate
  and remain that way?
• the threshold of AMPA receptors on the
  postsynaptic neuron becomes more sensitive, AMPAs
  fire more easily and unblock Mg, then NMDAs
  cause postsynaptic neuron to fire
• more receptors may be built
• some presynaptic changes may occur perhaps
  leading to release of more Glutamate

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Neurons throughout brain show changes with
experience. LTP mechanism appears to be active in
many different brain areas, specifics vary. Other
important neurotransmitters and receptor types
GABA, acetylcholine, opiates and others
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• Ampakines a structurally diverse family of
  small molecules that positively modulate
  AMPA-type glutamate receptors and enhance fast,
  excitatory transmission throughout the brain.
• But, downside?
• A surprise do not cause seizures or excitotoxic
  damage in animals
• Plus
• ampakines facilitate the formation of LTP
• regulate neurotrophin expression in the cortex
  and increase production of growth factors
• may help treat neurodegenerative conditions
  (Alzheimers) and certain psychiatric disorders
  (depression) which are hypothesized
• to involve insufficient levels of neurotrophins
  (BDNF)

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Lynch, 2006
Possibility and hope - ampakines may decrease
the amount of training needed for learning and/or
produce this effect along with an increase in the
strength of memory.
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• So how can they be all good?
• act in a highly selective way
• ampakines selectively facilitate the assembly of
  cortical networks needed to respond to present
  behavioral demands
• drug-induced increases in brain-derived
  neurotrophic factor (BDNF) are associated with
  improved performance, improved neurological
  function in animal models of Parkinsons disease
  increased neurogenesis protection against
  excitotoxicity reduced depression
• plus, positive modulation of the AMPA receptor
  shift dose-response curves for the therapeutic
  effects of drugs that operate on biogenic amines
  by as much as fivefold - may help
  antidepressants work at much lower doses