The Lateral Septum, in green, turns
the volume
up or down in aggression
Today’s post started by me checking
for anything new in the research about the hormone Vasopressin and autism. I
was surprised by just how much research continues to be published on the
subject – no smoke without fire, perhaps.
We also get another insight into how
aggressive raging develops in the brain; we even have a photo.
A novel therapy for Fragile-X is also
thrown into the mix, due to a link to oxytocin.
So, what is cooking in the research?
The first thing to note is that you
really do have to look at both Oxytocin and Vasopressin, because these two
hormones are very closely related.
We have previously looked at the
autism gene NLGN3, this gene encodes the cute sounding neuroligin-3.
https://epiphanyasd.blogspot.com/search/label/neuroglin
The reason
people with Fragile-X have autism is because they lack the protein FMRP (Fragile X mental retardation protein).
In
healthy neurons, FMRP modulates the local translation of numerous synaptic
proteins. Synthesis of these proteins is required for the maintenance and
regulation of long-lasting changes in synaptic strength. In this role as a
translational inhibitor, FMRP exerts profound effects on synaptic plasticity.
When you look at the interactions of
the FMRP protein you can find ways to compensate for this deficiency. This is nicely illustrated in the graphic
below. You just need to find another way to influence elF4E and elF4G.
Some people have told me they find these charts a bit overwhelming, but they precisely show what is going on. You just have to look up all the terms, you do not know. In the chart below there is NF1 autism, there is PTEN autism, problems with Ras are called RASopathies and cause MR/ID plus autism. We have at least one reader with TSC (Tuberous sclerosis) type autism. We have readers whose kids lack FMRP, because they have Fragile-X syndrome.
Today we see that an inhibitor of MnK (in yellow in the chart below) is another via option to treat Fragile-X.
Beyond Fragile-X, we can see that
numerous other upstream dysfunctions in the chart can result in miss-expression
of neuroligins (NLGNs) in the chart below and then result in autism.
One of the papers below goes further
and suggests
“This
work uncovers an unexpected convergence between the genetic autism risk factor
Nlgn3, translational regulation, oxytocinergic signalling, and social novelty
responses”
“We
propose that pharmacological inhibition of MNKs may provide a new therapeutic
strategy for neurodevelopmental conditions with altered translation
homeostasis”
“Our
work not only highlights a new class of highly-specific, brain-penetrant MNK
inhibitors but also expands their application from fragile X syndrome to a
non-syndromic model of ASD”
Regarding Fragile
X
“Collectively, this work
establishes eFT508 (an MNK inhibitor) as a potential means to reverse deficits
associated with FXS.”
What is
the connection to Oxytocin?
A problem with your neuroligins causes an impairment in oxytocin
signalling.
The role
of the Lateral Septum (LS) in both aggression and desirable social behavior
If you scan through the research on
vasopressin and oxytocin you will eventually come across references to the
LS. The LS is a part of your brain
called the Lateral Septum.
In the picture below you see a mouse
brain and the green part is the Lateral Septum (LS).
Source: https://neurosciencenews.com/rage-lateral-septum-3637/
“Our
research provides what we believe is the first evidence that the lateral septum
directly ‘turns the volume up or down’ in aggression in male mice, and it
establishes the first ties between this region and the other key brain regions
involved in violent behavior”
Both
social bonding and offensive aggression involve vasopressin receptors in a part
of the brain called the Lateral Septum (LS).
Activity in the Lateral Septum (LS) is regulated by inhibitory GABA,
and excitatory glutamate.
There
is a notable difference between males and females, at least in rats. No sex differences
were found in extracellular GABA concentrations during social playing; however,
glutamate plays a major role in female social playing. When glutamate
receptors are blocked in the LS pharmacologically, there is a significant
decrease in female social playing, while males had no decrease in playing. This
suggests that in the lateral septum, GABA neurotransmission is involved in
social play behavior regulation in both sexes, while glutamate
neurotransmission is sex-specific, involved in regulation of social play only
in females.
Aggressive
behavior in females
These models allowed me to investigate the role of the brain
oxytocin (OXT) and vasopressin (AVP) systems on aggressive behavior. Both
neuropeptides are known to regulate social including aggressive behaviors in
males and lactating females.
Taken together this part of my thesis shows that the balance between OXT and AVP
release within the LS regulates female aggression in a receptor and
region-specific manner via modulating GABAergic neurotransmission.
Overall, this thesis shows that females are able to develop escalated as well as abnormal aggression
just like males. In addition, the OXT and the AVP system seem to be main
players in regulating aggressive behavior in female Wistar rats, especially, regarding
their role in controlling aggression by acting on the LS.
The effect of Vasopressin as a therapy
Intellectual
and social disabilities are common comorbidities in adolescents and adults with
MAGE family member L2 (MAGEL2) gene deficiency characterizing the
Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and
molecular mechanisms underlying the risk for autism in these syndromes are not
understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency
and whether a treatment with vasopressin could alleviate the disabilities of
social behavior. We used Magel2-knockout mice (adult males)
combined with optogenetic or pharmacological tools to characterize disease
modifications in the vasopressinergic brain system and monitor its impact on
neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and
projections in the lateral septum were inappropriate for performing a social
habituation/discrimination task. Mechanistically, the lack of
vasopressin impeded the deactivation of somatostatin neurons in the lateral
septum, which predicted social discrimination deficits. Correction of
vasopressin septal content by administration or optogenetic stimulation of
projecting axons suppressed the activity of somatostatin neurons and ameliorated
social behavior. This
preclinical study identified vasopressin in the lateral septum as a key factor
in the pathophysiology of Magel2-related neurodevelopmental syndromes.
In
humans, intranasal administration of AVP increased activity in the LS and reciprocated
social collaboration (47). Intranasal
OXT administration enhances the suppression of oscillatory activity (8–25 Hz)
during execution and observation of social actions (48). Altogether,
OXT- and AVP-dependent modulation of neural activity in response to social
stimuli directly affect EEG activity, which may have a predictive value for the
impact of such treatment in ASD-associated disorders. Furthermore, an imbalance
between inhibition and excitation is associated with ASD, and AVP treatment
could reset the balance by altering the functions of SST neurons (49).
Predicting
Autism measuring Neonatal CSF
vasopressin concentration
We have yet another predictor of future autism.
Neonatal CSF vasopressin concentration predicts later medical record
diagnoses of autism spectrum disorder
The Russian paper below is very thorough. At least in the
case of autism, I do not agree with the therapeutic implications. The paper suggests Oxytocin agonists (like
oxytocin itself) and Vasopressin antagonists.
I propose Oxytocin agonists and Vasopressin agonists, as
a practical solution today. It is not a
perfect solution, but totally doable today.
Oxytocin (OXT) and arginine-vasopressin (AVP)
are structurally homologous peptide hormones synthesized in the hypothalamus.
Nowadays, the role of OXT and AVP in the regulation of social behaviour and
emotions is generally known. However, recent researches indicate that peptides
also participate in cognitive functioning. This review presents the evidence
that the OXT/AVP systems are involved in the formation of social, working,
spatial and episodic memory, mediated by such brain structures as the
hippocampal CA2 and CA3 regions, amygdala and prefrontal cortex. Some data have
demonstrated that the OXT receptor's polymorphisms are associated with impaired
memory in humans, and OXT knockout in mice is connected with memory deficit.
Additionally, OXT and AVP are involved in mental disorders' progression.
Stress-induced imbalance of the OXT/AVP systems leads to an increased risk of
various mental disorders, including depression, schizophrenia, and autism. At
the same time, cognitive deficits are observed in stress and mental disorders,
and perhaps peptide hormones play a part in this. The final part of the review
describes possible therapeutic strategies for the use of OXT and AVP for
treatment of various mental disorders.
4.4. Autism
Autism spectrum disorder (ASD) is a group of disorders that
are characterized by early disturbances of social communication and limited,
repetitive behaviour. Individuals with autism have impaired social cognition
and social perception, executive dysfunction, and atypical perceptual and
information processing. Additionally, they exhibit atypical neural development
at the systems level . Autism is characterized by a
disturbance of social interaction first of all, but it is also characterized by
cognitive dysfunctions, including working memory impairment. The OXT/AVP system plays a role in such deficits. In male mice with a
mutation in the Magel2 gene, social behaviour and cognitive functions are
disrupted in adulthood, which makes this model similar to ASD. The lack of
Magel2 causes a change in the OXT system. Subcutaneous administration of OXT to
mice with this mutation during the first week of life suffices to restore
normal social behaviour and learning abilities in adult mice. Exogenous OXT
stimulates the release of endogenous OXT and inhibits the accumulation of
intermediate forms of OXT (this is observed in OXT neurons in mice with the
Magel2 mutation). This was revealed by neuroimaging methods. Human ASD is associated with altered face processing and decreased
activity in brain areas involved in this process. OXT enhances the importance
of social stimulus in ASD, and probably can stimulate face processing and eye
contact in people with ASD. Genetic polymorphisms of the
OXT and AVP receptor genes are associated with ASD. Additionally, this review revealed a link between
social cognition disorders in autism and some SNPs in the OXTR and V1a receptor
genes. The most significant associations between SNPs in OXTR and social
cognition were found for rs2254298, rs53576 and rs7632287. SNP rs2254298 has
been associated with a diagnosis of ASD. SNP in the V1a receptor gene,
rs7294536, is closely associated with a deficit in social interactions. In addition, OXTR rs237887 polymorphism affects facial
recognition memory in families with autistic children.
Fig 1. The role of oxytocin and vasopressin systems in the
pathogenesis of mental disorders. Stress activates the HPA axis and rises in
plasma glucocorticoid levels, which leads to social through the cortisol
release. HPA axis activation increases the risk of development of
psychopathologies. OXT and AVP regulate emotional behaviours, multiple aspects
of social behaviour and cognitive functions. Negative environment, including
stress factor, causes an imbalance of the OXT/AVP system, which also leads to
psychopathological behaviour: aggression, social impairment, anxiety, emotional
and cognitive disorders. At the same time, the OXT/AVP system forms a reaction
to stress oppositely. OXT inhibits the HPA axis stress induced activity
(anxiolytic effect). AVP activates the HPA axis (anxiogenic effect). OXT and
AVP can be used as the treatment of mental diseases associated with social and
cognitive dysfunctions. OXT – oxytocin; AVP – arginine-vasopressin; iOXT –
intranasal oxytocin; iAVP – intranasal arginine-vasopressin; ACTH -
adrenocorticotropic hormone; CRH – corticotropin releasing hormone; HPA axis -
hypothalamic-pituitary-adrenal axis.
5. OXT and AVP systems in mental disorder treatments in
recent years, interest in the usage of OXT as the treatment of various
psychiatric diseases is growing. OXT and AVP systems that exist in balance
produce the contrary effect on emotional behaviour. Positive social stimuli
and/or psychopharmacotherapy can shift this balance towards OXT and can help to
stimulate emotional behaviour and restore mental health through this shifting.
OXT produces an effect on several neurobiological systems, including the HPA
axis, limbic system, neurotransmitters, and immune processes related to stress
disorders. The exact effects of iOXT still remain unclear; nevertheless, it is
known that iOXT action depends on individual sensitivity. Data from functional
magnetic resonance imaging demonstrated that iOXT induces temporary activation
of some cortex areas and prolonged activation of hippocampus and forebrain
areas. These structures are characterized by a high density of OXT receptors.
At the same time, iAVP causes stable deactivation in the parietal cortex,
thalamus, and mesolimbic pathway. Importantly, the intravenous administration of OXT and AVP does not
repeat activation patterns caused by intranasal administration of OXT and AVP.
Nevertheless, it is possible that a small amount of OXT which crosses the
blood-brain barrier may lead to an additional central OXT release since OXT is
able to bind to brain OXT ergic neurons and cause its own release. Generally,
OXT doses administered in studies vary from 15 IU to more than 7000 IU. As the
table indicates, the results of these studies are very different. The most
frequently used dose is 24 IU. Many studies are focused on the capability of
OXT in the treatment of depressive disorders. It was demonstrated that iOXT
reduces the time of concentration on aggressive facial expressions and
increases the time of concentration on happy faces in men and women with
chronic depression. Therefore, iOXT regulates emotion recognition in
depression. iOXT can be used in combination with antidepressants, enhancing
antidepressant efficiency. iOXT administration positively affects mother-child
relationship in mothers with postpartum depression (PPD). iOXT activates the protective
behaviour of mothers with PPD towards their children. Similar results were
found in animal experiments. In rats, iOXT reduced the depressive-like
behaviour in adult animals subjected to early maternal separation. Moreover,
the research of specific neurogenesis markers Ki67 and BrdU demonstrated that
iOXT promotes hippocampal neurogenesis, which is impaired in depressed rats. Many studies investigate the
therapeutic properties of iOXT and iAVP for the treatment of schizophrenia and
autism. It is known that schizophrenia disturbs social behaviour; and
cognitive function. iOXT has the potential for usage as a therapeutic tool to
restore impaired functions during schizophrenia. Some data suggest that iOXT
reduces the negative symptoms of schizophrenia, improves working memory, verbal
memory and cognitive function, and also improves social function in patients
with schizophrenia and schizoaffective disorder. Although many studies indicate
a positive effect of iOXT on cognitive function in people with schizophrenia,
the neuropeptide has a very selective action on behaviour. The exact mechanism
of iOXT action is also indefinite; therefore, its therapeutic potential
requires further research. Eventually, iOXT can be used as an additional
therapeutic agent in traditional schizophrenia treatment. iOXT can also be
applied to ASD treatment. It was found that iOXT improves social abilities in children
and emotionality in adult men with ASD. Moreover, the improvement of emotional
state was observed in adults after an 8 IU dose, but not after 24 IU. The study
of iOXT's therapeutic properties was also carried out using a mouse valproate
autism model. iOXT improved social behaviour in that model, and reduced
anxiety, depressive-like behaviour, and repetitive behaviour. iOXT has some
positive effects in the ASD treatment. Despite this, studies of the potential
therapeutic usage of iOXT are still at an early stage, and doctors have
insufficient data to prescribe iOXT to patients. A few data indicate the
therapeutic possibilities of AVP compared to OXT. It is known that iAVP was
used in the treatment of the first episode of schizophrenia, in addition to the
traditional benzodiazepine treatment. Cognitive functions (namely the
memorization process, long-term and short-term memory) improved in patients.
iAVP treatment ameliorated social ability in children with ASD. Additionally,
iAVP treatment reduced anxiety and repetitive behaviors in these children.
These data indicate the necessity of further investigation of AVP's treatment
potential.
A
fundamental challenge in developing treatments for autism spectrum disorders is
the heterogeneity of the condition. More than one hundred genetic mutations
confer high risk for autism, with each individual mutation accounting for only
a small fraction of cases1-3. Subsets of risk genes can be grouped
into functionally related pathways, most prominently those involving synaptic
proteins, translational regulation, and chromatin modifications. To attempt to
minimize this genetic complexity, recent therapeutic strategies have focused on
the neuropeptides oxytocin and vasopressin4-6, which regulate
aspects of social behaviour in mammals7. However, it is unclear
whether genetic risk factors predispose individuals to autism as a result of
modifications to oxytocinergic signalling. Here we report that an
autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired
oxytocin signalling in dopaminergic neurons and in altered behavioural
responses to social novelty tests in mice. Notably, loss of Nlgn3 is
accompanied by a disruption of translation homeostasis in the ventral tegmental
area. Treatment of Nlgn3-knockout
mice with a new, highly specific, brain-penetrant inhibitor of MAP
kinase-interacting kinases resets the translation of mRNA and restores oxytocin
signalling and social novelty responses. Thus, this work identifies a convergence between the genetic
autism risk factor Nlgn3, regulation of translation, and oxytocinergic
signalling. Focusing on such common core plasticity elements might provide a
pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this
would enable mechanism-based stratification of patient populations to increase
the success of therapeutic interventions.
Social recognition and communication are crucial elements in
the establishment and maintenance of social relationships. Oxytocin and
vasopressin are two evolutionarily conserved neuropeptides with important
functions in the control of social behaviours, in particular pair-bonding and
social recognition7,8 . In humans, genetic variation of the oxytocin receptor
(OXTR) gene is linked to individual differences in social behaviour9 .
Consequently, signalling modulators and biomarkers for the oxytocin or
vasopressin system are being explored for conditions with altered social
interactions such as autism spectrum disorders (ASDs)5,6 . In mice, mutation of
the genes encoding oxytocin or its receptor results in a loss of social
recognition and social reward signalling10–14. Mutation of Cntnap2, a gene
linked to ASD in humans, resulted in reduced levels of oxytocin in mice, and
the addition of oxytocin improved social behaviour in this model15. However, the vast majority of genetic
risk factors for autism have no known links to oxytocinergic signalling.
Thus, modification of translation homeostasis in Nlgn3KO
mice by MNK inhibition restores oxytocin responses and social novelty
responses. This work uncovers
an unexpected convergence between the genetic autism risk factor Nlgn3,
translational regulation, oxytocinergic signalling, and social novelty
responses. Although loss of Nlgn3 impairs oxytocin responses in VTA DA
neurons, the behavioural phenotype does not fully phenocopy genetic loss of
oxytocin. Oxytocin knockout mice exhibit impaired habituation in the social
recognition task10, whereas Nlgn3KO mice habituate normally but exhibit a
selective deficit in the response to a novel conspecific. This is probably due
to differential roles of Nlgn3 and oxytocin across several neural circuits and
over development. Moreover, Nlgn3 loss-of-function also affects signalling
through additional GPCRs23. We
propose that pharmacological inhibition of MNKs may provide a new therapeutic
strategy for neurodevelopmental conditions with altered translation
homeostasis. Notably, MNK loss-of-function appears to be overall well
tolerated. MNK1/2 double-knockout mice are viable46 and several MNK inhibitors
are entering clinical trials for cancer therapy47. Previously available MNK
inhibitors were greatly limited by specificity and brain penetrance. Our work not only highlights a
new class of highly-specific, brain-penetrant MNK inhibitors but also expands
their application from fragile X syndrome41 to a non-syndromic model of ASD.
The common disruption in translational machinery and phenotypic rescue in two
very different genetic models indicate that genetic heterogeneity of ASD might be
reduced to a smaller number of cellular core processes. This raises the possibility that pharmacological
interventions targeting such core processes may benefit broader subsets of
patient populations.
Fragile X
syndrome (FXS) is the most common inherited source of intellectual disability
in humans. FXS is caused by mutations that trigger epigenetic silencing of
the Fmr1 gene. Loss of Fmr1 results in
increased activity of the mitogen-activated protein kinase (MAPK) pathway. An
important downstream consequence is activation of the mitogen-activated protein kinase interacting protein
kinase (MNK). MNK
phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E
(eIF4E). Excessive phosphorylation of eIF4E has been directly implicated
in the cognitive and behavioral deficits associated with FXS. Pharmacological reduction of
eIF4E phosphorylation is one potential strategy for FXS treatment. We
demonstrate that systemic dosing of a highly specific, orally available MNK
inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in
mice. eFT508 resolves a range of phenotypic abnormalities associated with FXS
including macroorchidism, aberrant spinogenesis, and alterations in synaptic
plasticity. Key behavioral deficits related to anxiety, social interaction,
obsessive and repetitive activities, and object recognition are ameliorated by
eFT508. Collectively, this
work establishes eFT508 as a potential means to reverse deficits associated
with FXS.
Conclusion
I think I
have written enough about Oxytocin and Vasopressin.
The research is not entirely consistent
regarding Vasopressin, but my assumption is that for my kind of autism I want an
Oxytocin Agonist and a Vasopressin Agonist, some people might think it would be
a Vasopressin Antagonist.
The good news is that there is
significant research in humans, reported in previous posts, to support the use
of both Oxytocin Agonist and a Vasopressin Agonist
I also
think there will be both short-term, or immediate effects, from both treatments
but also potentially different long-term effects from continued therapy, that
is indeed suggested by the animal research models. For example, neurite
outgrowth is stimulated by oxytocin. It
is suggested that oxytocin may contribute to the
regulation of scaffolding proteins expression.
Is it worth
using oxytocin as a therapy to generate some extra hugs? You can argue both
ways, but the longer-term benefits of correcting low oxytocin levels may be
more profound.
The effects of
vasopressin and oxytocin are somewhat overlapping. We know that low levels of
vasopressin in spinal fluid are a good marker for autism, so putting a little
extra vasopressin in the brain does not seem unreasonable.
As usual with the human body, the
effects of oxytocin and vasopressin are different within the brain and in the
rest of your body. Also, the levels of
these hormones in your blood are not a good predictor of their levels within
the brain. This is a reoccurring
problem. Because taking a spinal fluid sample
is an invasive procedure, it is rarely taking place and then endless time and
money is wasted on blood tests that may well send the doctor in the wrong
direction, or just no direction.
It is highly likely that increasing
Oxytocin and Vasopressin in the brain is going to affect aggressive behaviors,
via actions in the Lateral Septum (LS).
Due to the role of GABA potentiating activity in the Lateral Septum (LS)
you might expect a possible difference in bumetanide-responders and bumetanide non-responders
(because GABA is acting as excitatory).
I would consider Oxytocin and
Vasopressin as fine-tuning autistic behavior and you would have to personalize
the dosage. In some people it might be a case of either or, rather than both.
Using MNK inhibitors to treat human
Fragile-X looks a great idea and hopefully a commercialized therapy could then
be trialed in broader autism.
