The Kandel lab’s paper was completely focused on the effect
of straitum D2 receptors on the PFC abnormalities relating to schizophrenia. I
really liked the introduction in the paper as it applied to some of the broader
questions I had about the validity of these studies. One of the bigger problems
I had with (maybe understanding the impact of) the papers is that I am not
completely sure how accurate the current state of the model for schizophrenia
is in mice, as Schizophrenia development is very complex and not wholly
understood in humans. The authors did mention that the model is one of the
biggest challenges in their tests
because of the complexity in both the genetic and physiological components.
(ask- are there no naturally occurring mental diseases in animals) Things such
as the DISC-1 gene and decreased levels of ANK3 in the hippocampus have been
linked with schizophrenia providing genetic causes, but the wide range of
symptoms in schizophrenia doesn’t seem to be justified by the model described
in this paper. I understand that since the continuation of the symptoms
persists after switching off the transgene, with doxycycline, developemental
expression causes certain symptoms but am not sure if a specific “trigger” is
needed to actually start the presentation of symptoms. The dopamine hypothesis of schizophrenia was
based on the early anti-psychotics , DA
antagonists, that worked on D2 but they usually alleviated certain positive
symptoms, while having no real effect on the negative symptoms- again –
bringing into question the accuracy of the animal models, again – as they mentioned,
DA problems are associated with many diseases. It would also be cool to see
what time the mice developed the symptoms (expressed in humans at ages 15-35),
just for curiosity’s sake (not sure if the 28 days they listed as meeting
criteria qualifies for this). I was happy that they discussed the D2
overexpressed mice as being a step towards building a complete endophenotypic
mouse model in the discussion, as it seems to acknowledge the problems they
encounter in the field as well.
The paper establishes their support for striatal D2-R’s
effect on D1 in PFC, turnover and so on – what affects working memory. I am not
sure why working memory is such a big deal in schizophrenia studies, as I do
not see why short-term memory is being utilized as a measure of schizophrenic
symptoms. Their explanation of “the cognitive deficit may reside in an
imbalance in the activation of D1 receptors in the PFC “ doesn’t really make
sense to me. However, the results presented in Figure 4, showing behavioral,
and working memory deficientcy do establish support for their point. I was
also a little surprised by some of the results they found, for example, in
Figure 3, they found that the overexpression of D2 –Rs did not change
locomotion and anxiety- which I kind of expected ( parkinsons- increased DA –
locomotion problems) . In Figure 6- they observed that D2 overexpression didn’t
cause obvious morphological changes- which seems very interesting as that goes
along with the way humans don’t express symptoms despite having morphological
differences ( abnormal pyramidal neuron lining in hippocampus, larger
ventricles, etc. ) . Also the changed DA transmission observed in Fig. 6C would
match the problems seen in things like COMT and MAO in schizophrenic patients. Finally,
although some of their data had low significances, the fact that it was
approved by reviewers and that they sourced many articles talking about how D2
overexpression has been given a lot of support in the development of
schizophrenia makes me think that their results are valid. They did use a lot
of behavioral assays and have a lot of data, with great interpretation as well.
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