My name is Shergi Zahid and I am an
undergraduate senior here in the lab, majoring in Biochemistry/Molecular
Biology. This is my second semester working in the lab and it has been a blast!
My latest assignments in the lab include reconstructing medium spiny neurons
(MSNs) and rendering them into realistic computational models, which we can use
to develop biophysical model and analyse their fine morphology. It’s actually
pretty interesting. But you know what is even more interesting? Some of the
publications our lab has produced! I would like to present to everyone a paper
published in the Journal of Neuroscience on January 24, 2018, titled “Neuronal glutamate transporters control dopaminergic
signaling and compulsive behaviors”. This paper is still very relevant to
our current work in the lab so it should be good for anyone who’s interested in
joining us to not only read the paper but also read this blog post to help you
better understand the research we’re conducting here. I’m going to try to keep
this as simple as possible to not scare anyone away. So to get started, what is
the premise of this whole study? To start, the focus of the study is on the neuronal
glutamate transporter EAAC1 and its impact on signaling and stereotyped
behaviors associated with obsessive compulsive disorder (OCD). The region of
the brain that our study focuses on is the striatum. It is the part of the
brain that controls execution of stereotyped movements. This region of the
brain is hyperactive when examining the brains of OCD patients. In normal
brains, EAAC1 is largely expressed in the striatum. Its loss is associated with
increased execution of ritual and anxiety-like behaviors in mice. But what are
molecular the mechanisms behind these behaviors? The paper addresses this exact
question. Through electrophysiological,
viral and molecular techniques as well as behavioral studies that were done on
mice, we found the explanation to this question. When explaining the molecular
mechanism of these behaviors we must look at two receptors found in the brain
that we had described to be associated with EAAC1, group I metabotropic
glutamate receptors (mGluRI) and D1 dopamine receptors (D1R). Here’s the basic
idea, when EAAC1 is expressed, it reduces the activation of mGluRI receptors
which results in increased D1R expression, this ultimately leads to long term
potentiation (LTP) leading to normal signaling activity in the striatum. When
observing mice with the EAAC1-/- you wouldn’t see this type of
result. However, if you blocked mGluRI, D1R expression would be restored.
Interestingly enough, when we have an EAAC1 expressing mouse in which we can
activate signal cascades coupled to GluRI we are able to trigger a decrease in
D1R expression and increased stereotyped movement. Below is a quick and easy summary of
everything.
With EAAC1 = mGluRI Activation ↓ & D1R
Expression ↑ Leading to LTP
No
EAAC1 = blocked mGIuRI, Activation ↓ &
D1R Expression ↑ Leading to LTP
With
EAAC1= coupled mGluRI Activation ↑ & D1R Expression ↓ Leading to stereotyped
movement
No EAAC1 = mGIuRI Activation ↑ & D1R Expression ↓ Leading
to stereotyped
movement
Now
onto the behavioral part. We subjected mice of two different genotypes (WT and EAAC1-/-)
to a SHIRPA screening, which tests for general behavioral abnormalities. We
only found subtle motor deficiencies in EAAC1-/- mice. Although both
mouse strains had similar levels of motor activity, EAAC1‑/- mice
showed increased anxiety like behaviors. These differences could be detected
over a broad age range (P14- P35), in male and female mice alike. When analyzing
more specifically striatal controlled behaviors (e.g. grooming), we found that
EAAC1-/- groomed more frequently than WT mice. Together, these data
identify EAAC1 as a key regulator of striatal activity, movement execution and
anxiety, which are all disrupted in OCD.
So…if
you want to know more about how the brain works, at a very deep and detailed
level, this is the place to be!
Shergil Zahid
Shergil is the recipient of the
following award:
2019 Presidential Award for
Undergraduate Research
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