NMDARs, MAO A, and Pathological Aggression

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NMDARs, MAO A, and Pathological Aggression
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Pathological Aggression

• An extreme predisposition to aggressive
  outbursts in response to stress
• An important area of study
• Much of what we discuss seems to involve the
  victims of aggression
• However, on a societal level, this seems akin to
  studying the symptom, not the disease
• If we can understand the roots of aggression, can
  we perhaps prevent victimization? (resilience?)

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MAOA and Aggression

• Monoamine oxidase A
• Key enzyme which catalyzes deamination of
  serotonin (5-HT) and norepinephrine (NE) in the
  brain
• 5-HT, NE Neurotransmitters that play a role in
  stress response (see where Im going with this?)
• MAO A coded for by MAOA Gene
• First linked to aggression in humans with
  discovery of Brunner syndrome (1993)
• Syndrome characterized by nonsense mutation of
  gene, and predisposition to violent responses to
  unexpected stressors
• X-chromosome linked

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MAOA and Aggression

• More recent studies have shown at least six MAOA
  allelic variants exist
• All differ in terms of transcriptional efficiency
  (Sadeh 2012)
• Bortolato notes that male carriers of low
  activity variants are more susceptible to
  developing impulsive aggression as a result of
  early life trauma
• Severity of antisocial traits is inversely
  correlated with MAOA catalytic activity in brain
• MAOA Aggression

But how does this all work exactly?
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NMDARs

• N-methyl D-aspartate receptors
• Bortolato NMDARs serve a central function in
  the regulation of information processing, as well
  as aggressive and defensive responses.
• But what are they???
• Ionotropic channels for glutamate
• Control synaptic plasticity
• Basically a synapses ability to change in
  strength of response
• Affects memory and learning
• Made up of different subunits NR1, NR2A-D
• Subunit composition influenced by MAO
  neurotransmitters (Ah-ha!)

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Cliffand the lizards

• (No, not the name of a 1950s Doo-Wop Band)
• Cliff studied NMDAR subunits previously
• Used A. caroliniensis
• Exploited dominant/subordinate male hierarchy to
  elicit aggression in lizards
• Methodology
• Four treatment groups
• Paired Males (Dominant/Subordinate)
• Males injected with corticosterone (lizard stress
  hormone)
• Control
• Hypothesized that social stress would result in
  increase in NR2A, B, subunits in NMDAR in
  lizards medial pallium
• As would corticosterone

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Cliffs results
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NR2A, NR2B and Aggression

• Cliffs findings demonstrate how these subunits
  are linked to aggression in lizards
• Social aggression increased levels of these
  subunits more than injections of corticosterone
• And that was just over the course of one day,
  after social stress
• Bortolato builds upon this work
• Hypothesizes that the role of MAO A in reactive
  aggression may be mediated by alterations to
  these very NMDAR subunits
• Question to keep in mind If NR2A and NR2B are
  upregulated during social aggression, what would
  happen if they were already always at high levels?

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MAO A and NMDARs

• Bortolato set out to see what role MAO A had in
  reactive aggression through mediation of NDMARs
• Methodology
• Adult male mice, experimentally naïve, from gt 3
  litters
• Two Treatment Groups
• Wild Type
• MAO A Knockout
• Bortolato examines
• Neurotransmitter levels
• NMDAR subunit expression
• Effects of three NMDAR antagonists on
• Electrophysiology of NMDARs
• Locomotor activity
• Aggressive Behavior

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NMDAR Antagonists

• Antagonist drugs block or depress the responses
  of a receptor site, in this case, NMDARs
• Dizocilpine
• General NMDAR antagonist
• PEAQX
• NR2A subunit antagonist
• Ro 25-6981
• NR2B subunit antagonist

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Resident Intruder Test

• Resident Intruder Test
• MAO A KO males where isolated for 14 days in cage
  Then exposed to age/weight-matched WT males
• Measured
• Attack latency
• Attack duration
• Number of aggressive bouts
• Total locomotor activity (crossing superimposed
  grid)
• https//www.youtube.com/watch?vYpGRQeY1cx0

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Results 5-HT, NE Levels

• MAO A deficient mice showed significantly higher
  levels of serotonin and norepinephrine in the
  four brain regions measured
• Similar glutamate levels, dizocilpine binding to
  NDMARs

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Results NMDAR subunit expression (PFC)

• Significantly higher levels of NR2A and NR2B
  (similar to aggression effect in lizards
  hippocampus)

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Results Electrophysiological properties in NMDARs

• EPSC Excitatory Post-Synaptic Current
• Next slide shows MAO A KOs with significantly
  reduced EPSC decay time
• Reduced amplitude of NMDA EPSCs
• No change in minimum stimulus intensity
• Ill be honest, I dont really understand what
  this means
• But perhaps Torrie can enlighten us(?)

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Results NMDAR Antagonists and Locomotor Activity

• To explore behavioral impact of altered NMDAR
  function
• NMDAR antagonist dizococilpine increased
  locomotor activity in WT
• Niether NR2A, NR2B, or NMDAR antagonists were
  able to elicit significant locomotor changes

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Results NMDAR Antagonists and Behavior

• All antagonists caused increase in latency to
  attack, decrease in fighting bouts, and a
  decrease in fighting duration

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Discussion

• MAOA modulates aggressive behaviors by
  controlling structure and function of NMDARs
• NMDARs work as coincidence detector enables
  summation of converging inputs and processing of
  relevant information
• Reduced EPSC decay time and excitability impairs
  ability to process variable inputs from other
  synapses
• Cant put the emotional puzzle together
  susceptibility
• Results in inability to regulate emotional
  processing (negative bias)
• Problem Reason for increase in NR2A, NR2B
  remain unknown
• MAOA regulates balance of 5-HT and NE, so it
  could be because of increased monoamine levels,
  but
• Changes in NMDARs were only found in the PFC of
  mice, while 5-HT and NE were increased across the
  brains regions

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Discussion

• Despite uncertainty of causes, NR2A and NR2B
  levels certainly induced sensitivity to NMDAR
  antagonists
• These antagonists significantly decreased
  aggressive behavior
• Resilience
• Points to possible therapeutic options for
  treating reactive aggression
• In summary, the present findings highlight
  NMDARs as promising targets for treatment of
  antisocial aggressive traits in individuals with
  low MAOA activity. Future clinical studies are
  warranted to validate this intriguing possibility
  and fully establish the anti-aggressive
  properties of NMDAR blockers.
• So, thats great, and mean people suck and
  everything but why should I really care about
  any of this???

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Psychopaths

• Psychopathy is a multidimensional construct
  characterized by an interpersonally manipulative
  and emotionally detached personality profile that
  differentiates it from other antisocial
  syndromes
• Prone to impulsive, irresponsible and aggressive
  behavior
• Psychopathy is a popular theme in American
  culture, but misrepresents actual clinical data
• Still a real problem

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What makes a psychopath?

• Sadeh 2012 Gives a good rundown of genetic and
  environmental traits the contribute to
  psychopathy
• Gene-Environment Interaction
• Serotonin transmitter polymorphisms
• 5-HTTLPR short and long allele polymorphisms
• Has been associated with psychopathic-like traits
  in adults
• Heightened amygdalar activation and interpersonal
  affective traits, respectively.
• Low activity MAOA variants
• As demonstrated, linked to heightened aggression
• Childhood Abuse
• Generally associated with antisocial behavioral
  problems

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Genetic precursors for Psychopathy

• Sadeh administered a Psychopathy Screening
  Checklist to adult men who had antisocial and
  psychopathic traits
• Also did genetic evaluation for 5HTTLPR and MAOA
• Childhood Trauma Questionnaire
• Found that carriers of 5-HTT long allele, MAOA
  low activity variant had higher scores relating
  to antisocial, impulsive traits, often associated
  with psychopathy
• Although not correlated with childhood abuse,
  could not rule out gene-environment interactions
  due to the large number which could not be
  assessed

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Free Will/Determinism?

• https//www.youtube.com/watch?vxmAyxpAFS1s
• Skip to 4 minute mark