How do psychiatric drugs work?
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1. Statement of the problem: Antispychotics, Antidepressants, Bipolar drugs
2. Lessons from nAChRS; 3. Pharmacokinetics
4. Detailed hypotheses: Antipsychotic drugs SSRI Antidepressant drugs “Fast” NMDA blocker antidepressants
5. Tests of “inside-out” mechanisms for psychiatric drugs
Psychiatric drugs bind to classical targets within early exocytotic pathways: Therapeutic effects
Biological Psychiatry, Dec 2012 Henry A. Lester, Julie M. Miwa, and Rahul Srinivasan
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Disclaimer
This session deals with psychiatric disease.
Henry Lester is not a psychiatrist--not even a physician.
Don’t change any medical treatment that you might now be receiving on the basis of these lectures.
Don’t give any medical advice based on these lectures or problem sets.
0 2 4 6 8 10 12
Percent of Total
Disease Burden by Illness - Disability Adjusted Life Years
United States, Canada and Western Europe, 200015-44 year olds
Unipolar depressive disorders
Alcohol use disorders
Schizophrenia
Iron-deficiency anemia
Bipolar affective disorder
Hearing loss, adult onset
HIV/AIDS
Chronic OPD
Osteoarthritis
Road traffic accidents
0 2 4 6 8 10 16
Source: WHO – World Health Report, 2001
1. “The mood-elevating effects of fluoxetine [Prozac] are not evident after initial exposure to the drug but require its continued use for several weeks. This delayed effect suggests that it is not the inhibition of serotonin transporters per se, but some adaptation to sustained increases in serotonin function that mediates the clinical actions of fluoxetine. However, where these adaptations occur in the brain, and the nature of the adaptations at the molecular level, have yet to be identified with certainty.”
2. “All current antipsychotic drugs exert their full therapeutic actions over weeks, suggesting that, like lithium and antidepressants, slowly developing adaptations (in this case to initial D2 dopamine receptor blockade) are required for their antipsychotic effects.”
S. E. Hyman, E. Nestler, R. Malenka, 2008Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2nd Edition
How do psychiatric drugs work?
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Some psychiatric drugs, their targets, logP values, and half lives
fluoxetine (Prozac)
serotonin transporter logP 3.4, 24-72 hr
clozapine (Clozaril)5-HT2A serotonin receptor, GPCR
logP 3.2, 8-12 hr
ketamine (“special K”)
NMDA glutamate receptor logP 2.2, 3-5 hr
chlorpromazine (Thorazine)
dopamine D2 receptor, GPCRlogP 5.2, 16-30 hr
nicotine acetylcholine receptor
logP 1.2, 0.5 -2 hr
recreational / abused / addictive
antipschizophrenic antidepressant
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6
Population of US Public Mental Insitutions
0
100
200
300
400
500
600
1800 1850 1900 1950 2000 2050
yearth
ousa
nds
Each “advance” in biology has been tried out on schizophrenia.
Early 20th century, German classification & Nazi genetics
1950’s American psychiatrists (including Bettelheim) reacted with “schizogenic mother”
or “refrigerator mother” hypothesis
1950, Linus Pauling fractionated urine; 1968 “Orthomolecular Psychiatry” in Science
1955, chlorpromazine dopamine theories
1970, glutamate theories
1995, growth factors, development, migration
2000, genetics & genomics
2003, interneuron diversity
2005, inflammation
There is no satisfactory explanation yet.
Schizophrenia Pathophysiology
In general, modern theories of schizophrenia emphasize abnormal balance among
neuronal circuits or pathways, rather than individual neurons that either(a) degenerate or (b) fire too much or too little
Clinical potency of
“classical” or “typical”
antipsychotic drugs
correlates best
with
dopamine D2 receptor blocking dose
(Nestler, 16-6)
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Clinical potency of “classical” or “typical” antipsychotic drugs correlates with dopamine D2 receptor blocking dose . . .
. . . . but modern “atypical” antipsychotics also block other GPCRs (Nestler, 16-8)
Haloperidol Clozapine Quetiapine
Risperidone Olanzapine Sertindole
Affinity
D1 dopaminergic
D2 &D3 dopaminergic
Muscarinic cholinergic
5HT2A serotonergic
α1 adrenergic
α2 adrenergic
H1 histaminergic
Conventionals:
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Terrible side effects:
tardive dyskinesia (mesostriatal pathway) weight gain, agranulocytosis
Atypicals:
Major DepressionI. Symptoms: Depression is defined as the affective state of sadness that
occurs in response to a variety of human situations such as loss of a loved one, failure to achieve goals, or disappointment in love. Major depression differs only in intensity and duration or quality of the emotional state.
From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006
(“Anhedonia”)
II. Characteristics of Major DepressionA. Untreated episodes of major depression usually last from 7 - 14
months.B. Major depression is a recurring disorder, usually worsening with
age if not treated.C. The reported incidence of depression is 3 times higher in women
than in men.
Along with changes in mood, the symptoms of Major Depression include disruption of basic drives (eating and sleeping), as well as cognitive disturbances (ruminations, guilt, indecisiveness, persistent thoughts of suicide).
This constellation of symptoms suggest involvement of cortical structures, a number of limbic brain structures, including the hippocampus, amygdala, and mesolimbic dopamine neurons (“reward centers”), and also midbrain structures controlling appetite.
Depression involves dysfunction of many brain areas
From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006
Brain Areas that Regulate Mood
FC: Frontal cortex (esp. prefrontal and cingulate) - cognitive function, attention
HP: Ventral Hippocampus - cognitive function, memory
NAc: Nucleus Accumbens (ventral striatum) - reward and aversion
Amy: Amygdala - mediates responses to emotional stimuli
HYP: Hypothalamus regulates sleep, appetite, energy, sex
VTA: Ventral Tegmental Area - Sends dopaminergic projections to other areas
DR: Dorsal Raphe nuclei - send serotonergic input to other areas
LC: Locus Coeruleus - sends noradrenergic input to other areas.
I. The most successful medicines for treatment of Major Depression in recent years have been the selective serotonin reuptake inhibitors (SSRI’s)
II. SSRI’s include Prozac, Zoloft, Celexa, Paxil… These drugs inhibit the specific serotonin transporters that take up serotonin after it is released. Thus, the drugs are believed to increase serotonin levels in the brain.
III. Depression also is accompanied by misregulation of other neurohormonal pathways, for example the ACTH (pituitary) /cortisol (adrenal gland) pathway. NE and DA systems may also be misregulated.
IV. The SSRI’s are not effective for about half of cases of depression. Thus, we have much more to learn about the various causes of depression.
SSRI’s
Serotonergic systems in the brain
The midbrain Raphe nuclei
from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997
Rostral System
Caudal System
B6 and B7 are the Dorsal Raphe nuclei, which contain 5-HT neurons whose endings branch profusely and do not make “conventional” synapses. This fiber system is called the D-system.
B5 and B8 are the Median Raphe nuclei, which contain 5-HT neurons whose endings form repeated, more conventional synapses. This fiber system is called the M system.
Rostral System
from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997
B9 is also called the supralemniscal nucleus (SLN).
Two Serotonergic Fiber Types in the Forebrain Demonstrated by Immunocytochemical Labeling
D-System - small arrowsM-System - large arrows
Scale bar = 10 µm
from Tork, Ann. N.Y. Acad. Sci., 1990
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Bipolar Disease
1. Clinical description
2. Genetics
3. Possible causes
4. Heterozygote advantage?
5. Therapeutic approaches
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Bipolar disorder affects 1-1.5% of the
population in most modern societies.
Like depression, bipolar disorder is a
mood disorder. It was formerly termed
manic-depressive disorder, because
patients have one or more manic or nearly
manic episodes, alternating with major
depressive episodes.
1st episode often in mid-20’s.
Bipolar disorder often leads to suicide.
1. Clinical description, based on DSM-IV.
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From DSM-IV
Summary description of a manic episode
Manic Episode is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood. This period of abnormal mood must last at least 1 week (or less if hospitalization is required).
The mood disturbance must be accompanied by at least three additional symptoms from this list:
-inflated self-esteem or grandiosity,
-decreased need for sleep,
-pressure of speech,
-flight of ideas,
-distractibility,
-increased involvement in goal-directed activities or psychomotor agitation, and
Excessive involvement in pleasurable activities with likelihood of painful consequences
If the mood is irritable (rather than elevated or expansive), at least four of the above symptoms must be present . . . .
The disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterized by the presence of psychotic features . . . . .
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No single gene causes bipolar disorder.
Data for concordance among twins in bipolar disorder:
“narrow”
definition
“broad”
definition
monozygotic
(n = 55)79% 97%
monozygotic,
reared apart
(n = 12)
69%
dizygotic
(n = 52)24% 38%
2. Genetics
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Each new advance in neuroscience has been tried out on bipolar disorder--
as for schizophrenia.
There is no satisfactory explanation yet.
As for schizophrenia, present theories invoke:
circuit properties
early developmental events
rather than individual neurotransmitter systems.
3. Possible causes of bipolar disease
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Touched With Fire : Manic Depressive Illness and the Artistic Temperamentby Kay Redfield Jamison
"This is meant to be an illustrative rather than a comprehensive list . . .Most of the
writers, composers, and artists are American, British, European, Irish, or Russian; all
are deceased . . . Many if not most of these writers, artists, and composers had other
major problems as well, such as medical illnesses, alcoholism or drug addiction, or
exceptionally difficult life circumstances. They are listed here as having suffered from
a mood disorder because their mood symptoms predated their other conditions,
because the nature and course of their mood and behavior symptoms were
consistent with a diagnosis of an independently existing affective illness, and/or
because their family histories of depression, manic-depressive illness, and suicide--
coupled with their own symptoms--were sufficiently strong to warrant their inclusion."
4. Heterozygote advantage?
autobiography:An Unquiet Mind by Kay Redfield Jamison
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from JamisonKEY:H= Asylum or psychiatric hospital; S= Suicide; SA = Suicide Attempt
Writers Hans Christian Andersen, Honore de Balzac, James Barrie, William Faulkner (H), F. Scott Fitzgerald (H), Ernest Hemingway (H, S), Hermann Hesse (H, SA), Henrik Ibsen, Henry James, William James, Samuel Clemens (Mark Twain), Joseph Conrad (SA), Charles Dickens, Isak Dinesen (SA), Ralph Waldo Emerson, Herman Melville, Eugene O'Neill (H, SA), Mary Shelley, Robert Louis Stevenson, Leo Tolstoy, Tennessee Williams (H), Mary Wollstonecraft (SA), Virginia Woolf (H, S)
Composers Hector Berlioz (SA), Anton Bruckner (H), George Frederic Handel, Gustav Holst, Charles Ives, Gustav Mahler, Modest Mussorgsky, Sergey Rachmaninoff, Giocchino Rossini, Robert Schumann (H, SA), Alexander Scriabin, Peter Tchaikovsky
Nonclassical composers and musicians Irving Berlin (H), Noel Coward, Stephen Foster, Charles Mingus (H), Charles Parker (H, SA), Cole Porter (H)
Poets William Blake, Robert Burns, George Gordon, Lord Byron, Samuel Taylor Coleridge, Hart Crane (S) , Emily Dickinson, T.S. Eliot (H), Oliver Goldsmith, Gerard Manley Hopkins, Victor Hugo, Samuel Johnson, John Keats, Vachel Lindsay (S), James Russell Lowell, Robert Lowell (H), Edna St. Vincent Millay (H), Boris Pasternak (H), Sylvia Plath (H, S), Edgar Allan Poe (SA), Ezra Pound (H), Anne Sexton (H, S), Percy Bysshe Shelley (SA), Alfred, Lord Tennyson, Dylan Thomas, Walt Whitman
Artists Richard Dadd (H), Thomas Eakins, Paul Gauguin (SA), Vincent van Gogh (H, S), Ernst Ludwig Kirchner (H, S), Edward Lear, Michelangelo, Edvard Meunch (H), Georgia O'Keeffe (H), George Romney, Dante Gabriel Rossetti (SA)
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People with bipolar disorder are often fascinating in the early stages.
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1887 1887-88
Vincent Van Gogh 1853-1890750 paintings; 1600 drawings; 700 letters
Life history: born and raised in the NetherlandsParis 1886-88Arles 1888 (1st episode; cut off his own ear)hospitalized 1888-1890Auvers-sur-Oise 3 months. Shot himself 7/27/1890
1886
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I should like to do portraits which will appear as
revelations to people in a hundred years' time.
-- Letter to his sister Wil, 3 June 1890
Early 1889
Dr. GachetJune 1890
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July 1890
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29
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Surgery to remove large portions of the brain (1950’s-60’s)
Electroconvulsive shock therapy (ECT).
Now administered under anesthesia.
Various electrode placements, pulse widths, and frequencies
“In situations where medication, psychotherapy, and the combination of these
interventions prove ineffective, or work too slowly to relieve severe symptoms
such as psychosis (e.g., hallucinations, delusional thinking) or suicidality,
electroconvulsive therapy (ECT) may be considered. ECT is a highly effective
treatment for severe depressive episodes.“
-- National Institute of Mental Health
Over a hundred theories have been offered to account for the efficacy of ECT.
http://www.acnp.org/G4/GN401000108/CH106.html
5. Therapeutic approaches to bipolar disorder
Surgical and electrical intervention
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Li+ ion
Therapeutic effects begin in ~ 5 d, require several wk.
Li+ is quite poisonous at higher doses.
Valproic acid and other anticonvulsants
These also require several wk for full effects.
Therapeutic approaches to bipolar disorder
Drugs(upper left-hand regionof the periodic table)
32
1. We don’t know, but there are now some good guesses.
2. All ideas about Li+ assume an intracellular target.
Li+ enters cells freely through several channels and ion-coupled transporters
that normally serve for Na+.
Intracellular concentrations of Li+ are probably several mM.
3. Most ideas about Li+ involve enzyme inhibition.
Most of the suspected enzymes manipulate high-energy phosphate bonds.
How does Li+ act?
Three exemplar patients in the early days of Li+
Contemporary ideas about psychiatric drugshave emphasized binding to
the classical targets at synapses. . .
“Inside-out” mechanisms emphasize binding to the same classical targets, but within the
endoplasmic reticulum and cis-Golgi
BloodLungs
H+
Like most drugs, nicotine is a weak base.Its neutral form passes through 6 plasma membranes in ~ 20 s
logP = 1.1 = log (solubility in octanol / water) 34
NH+
N
N
N
N
N
CSF
Alvelolarepithelium
Brain capillary
35Nucleus
UPRE
PlasmanACh
R
Nicotine in CSF
Classical Pathway:Channel activation & desensitization
→ Do neurons survive Despite stressors?
Unfolded protein response
membrane
COPII vesicleSec 13/31
Sar1Sec24Sec23
ATF6
Golgi
PharmacologicalChaperoning→ upregulation
M3-M4 loop
H+ +
ERBiP
PERKIRE1
Clathrin
Secretory vesicle
COPII
Golgi complex
COPI
Early endosome
COPI
Lysosome
Ca2+
Na+
“Inside-out” Drug Action by Nicotine at α4β2 nAChRs
NH+
N
H+
N
N
Endoplasmic reticulum
nAChR
ATF6
IRE1
XBP1
eIF2α
PERK
ATF4
1. Agonist binding eventually favors stable, high-affinity states (a “chaperone”)
106
channels
nicotine20 sec
Three possible results of nicotine-nAChR binding in the endoplasmic reticulum
“closed”
AC Highest affinity
Fre
e E
ne
rgy
Reaction Coordinate
“activated”
“desensitized”
Bound states with increasing affinityunbound
agonist
?
2. Nicotine binding at subunit interface favors assembled nAChRs (a “matchmaker”)
3. Nicotine may displace lynx, directing nAChRs toward cholesterol-poor domains (an “escort”)
nicotine
lynx
36
R. L. Wiseman, C. M. Haynes, D. Ron Cell 2010
The three arms of the ER stress / unfolded protein response pathway
37
38
During chronic exposure to nicotine, α4β2 nAChRs are selectively upregulated.
Pharmacological chaperoning is necessary but not sufficient for upregulation.
Other sequelae of chaperoning: changed stoichiometry, reduced ER stress and reduced UPR.
Upregulation proceeds similarly in clonal cells, rodent brains, and smokers’ brains.
Inside-out Pharmacology of Nicotine Effects at α4β2 nAChRs
Now we’re assessing gene expression in identified neurons chronically exposed to nicotine.
Inside-out pharmacology is a powerful concept for nearly all CNS drugs:They are all membrane-permeant weak bases.
The discovery criteria for psychiatric drugs lead to excellent intracellular chaperoning
1. High bioavailability implies high membrane permeationAll psychiatric drugs have logP > 2
2. Good stability in the body implies simple or little enzymatic breakdown.Half-life is ~ 1 day.
3. Good selectivity, few off-target effects imply high-affinity binding to the targetKd < 1 μM, often ~ 10 nM
a. “Chaperoning”: (i) Transporter ligands are
organic substratesions,or antagonists,
They favor two major binding states, “inward” vs “outward”.
(ii) GPCR ligands (see next slide): agonistsantagonistsallosteric modulators“inverse” agonists
b. “Matchmaking”:(i) Neurotransmitter transporters must homodimerize before leaving the ER(ii) GPCRs homo- and heterodimerize, in some cases required for ER export,
in some cases favored by ligands 39
Pharmacological chaperoning of GPCRs
40
receptor mutant /WT drug class reference
adenosine A1 mutant agonists; antagonists (Malaga-Dieguez et al., 2010)
dopamine D4 bothtransported dopamine; quinpirole; antagonists
(Van Craenenbroeck et al., 2005
)gonadotropin-
releasing hormonemutant antagonists
(Conn and Ulloa-Aguirre, 2011
)
histamine H2 both agonist, inverse agonist (Alewijnse et al., 2000)
opsin mutant -- (Noorwez et al., 2008)
δ-opioid mutant antagonist (Leskela et al., 2012)
μ-opioid mutant agonists, antagonists (Chaipatikul et al., 2003)
melanin conc. hormone
mutant antagonist (Fan et al., 2005)
melanocortin-4 both antagonist, inverse agonist (Tao, 2010)vasopressin V1a both antagonist (Hawtin, 2006)
vasopressin V1b/V3 both antagonist (Robert et al., 2005)vasopressin V2 both antagonists (Wuller et al., 2004)
Enzyme or
channel
Transcription factors
Nucleus
Intracellular messenger
kinase cascade
Drug
+ In CSF
+
Endoplasmic reticulum
GolgiH+
ATF6,
CREB-H
IRE1
XBP1
p-eIF2α
PERK
ATF4
NucleusUPRE
Drug
+ in CSF
Transcription factors
ATF6
+ +
Neutral permeant drug
+
+ +
+
BiP
PERKIRE1
++
H+
ER
Golgi
β-arrestin
A. Inhibition of plasma membrane GPCR , and downstream effects
B. Intracellular pharmacological chaperoning of GPCR, and downstream effects
Most papers suggest . . . We suggest . . .
Two mechanisms for gene activation downstream from antipsychotic drugs
“Nearly” cell-autonomous actions of SSRI antidepressant treatment
Kellermann group 42
43
Other diagrams
Samuels & Hen, Eur J. Neurosci, 2011
Adult Neurogenesis
Inside-out actions would occur here
Gene activation is too brief to account for the “therapeutic lag”
Axonal transport provides a natural delay in the “inside-out” mechanism.
Speed: ~ 1 mm / day.
Suggests that equivalent effects would require briefer delays in animals with shorter axons
44
Marks et al, 1985
Dendritically localized events
Days of nicotine infusion
Mouse hippocampus
45
How does acute ketamine produce antidepressant effects within 2 hr?
Monteggia & Duman groups suggest . . .
(1) involve BDNF synthesis & release, (2) occur in the dendrites,(3) require protein synthesis, (4) do not require gene activation.
The effects
NMDA Receptor
kinases↓
BDNFsecretion
BDNF mRNA
BDNF↑
Dendritic Golgi
Outside-in
Ca2++
Decreased Ca2+ flux
DendriticER
COPII
BDNF mRNA
p-eIF2α↓
pPERK↓
Escorting
BDNF secretion
BDNF↑
Inside-out
BiP
PERKIRE1
H+
+
ER
+ +
+
+ +
NMDA Receptor
NH2+
H3C
H+
O
Cl
NHH3C
O
Cl
We suggest . . .
“Acid trapping” of nicotine might1.keep nAChRs
desensitized untilthey are exocytosed;
2.serve as a reservoir for nicotine
Cell nACh
R membrane
Clathrin
Endoplasmic reticulum
nAChR
Secretory vesicle
COPII
Golgi complex
COPI
Early endosome
COPI
Lysosome
pH
5.2 100
6.0 30
6.7 3
6.3 20
6.5 10
7.2 1
nic+
nicCSF
Nicotine in CSF
NH+
N
H+
N
N
See detailed calculations for antipsychotics:Tischbirek et al, Neuron 2012
7.2 1 &
What knowledge do we need next?
As usual, we need cell biology & biochemistry
1. Reconstituted, cell-free systems for ER exit and retrieval
2.Better real-time markers for compartmentalized receptors and transportersa. Imaging mass spectrometryb. Plasma membrane binding only? Possible with impermeant derivativesc. ER binding only? More challenging, especially for antagonists.
3.Better measurements of pathway-specific gene activation (RNA-Seq)
4.Analyze newly synthesized proteins
47
Contemporary ideas about psychiatric diseaseshave emphasized synaptic and signaling deficits . . .
“Inside-out” mechanisms emphasize that ~30% of a cell’s proteins enter the ER,
and additional nuclear and cytoplasmic proteins control their synthesis & trafficking.
49
Polygenicthe disease occurs only if several genotypes are present together
Genetically Multifactorialseveral distinct genes (or sets of genotypes) can independently cause the disease
Partially penetrantnongenetic or epigenetic factors are required, or the disease is inherently stochastic
PolygenicGenetically Multifactorial
PartiallyPenetrant
Three concepts used in describing complex diseases such a schizophrenia
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Concordance for Lifetime Risk of Schizophrenia
0% 10% 20% 30% 40% 50%
general population
1st cousins
uncles/aunts
nephews/nieces
grandchildren
half siblings
parents
siblings
children
fraternal twins
identical twins
shared DNA
100%
50%(1st-degree relatives)
25%
12.5%
Like Kandel Figure 60-3
48%17%
1% (independent of culture)
Genetics(David Helfgott’s father; John Nash’s son)
51
GABAergic “chandelier cell” in human cerebral cortex hasmany large axon terminals . . .
DeFelipe, Brain (1999) 122, 1807 (Cajal Institute, Madrid)
PyramidalCells
Ch terminals
~ 100 μm
Ch terminals
Ch axon
. . . and plentiful somatic ER
Jones, J. Comp. Neurol., 1984
End of session
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