Download Synaptogenesis and the Proteins that influence its Connectivity

Synaptogenesis and the Proteins that influence its Connectivity
By: Dominique Johnson
Molecular Biology/ Biology 325
May 9, 2015
I hereby certify that this paper is free from plagiarism. I have documented all material, included
all references used in the proper format, cited any paraphrased material or direct quotes, and
enclosed direct quotes in quotation marks. I understand that violations of the plagiarism policy will
result in referral to the Bridgewater College Honor Council and possible disciplinary action.
Signed: Dominique Johnson
One may realize that as they age their cognitive abilities have significantly improved over
the years of their life. One is able to hold more information, pay more meaningful attention to
their environment, and as an adult or an older child one is able to learn complex subjects much
more quickly than that of an elementary school age child. This is all accomplished through a
process called synaptogenesis, or the development of new synapses. This process occurs right
after birth, infants develop new synapses at a rate of a million connections per second (1).
Synapses are formed based off of a “use it or lose it” mentality. This means that if that
connection is not used, it goes through a process called pruning which will get rid of the synapse.
How then is it that some synaptic connections are better connected compared to others? The
quality of a synaptic connection is based on the proteins that form that synapse. There are
proteins that guide parts of the neuron to their specific destination allowing for adhesive proteins
to hold the synapse together. These destinations include an axon to a postsynaptic neuron,
muscle, or organ. Then there are the proteins that function within the synapse itself, such as
SynCAM and neurotransmitters. The proteins that start synaptogenesis are Neuregulin and Nmethyle- D aspartate receptors, these are the proteins that guide the axon. (1, 2, 5, and 7).
Neuregulin (NRG1) and N-methyl-D aspartate receptors (NMDAR) play important roles
in various Neuronal functions. NRG1 is a transmembrane protein that is thought to regulate the
function of NMDAR in cortical neurons. This protein is a member of the neuregulin family,
which consist of four related genes (NGR1-4) (2). They are characterized by them all having an
epidermal growth factor (EGF) that activates EGF- receptors – related tyrosine kinases (ErbB)
(Osaki). NRG1 functions in migration of neurons, axon projection, myelination, and
neurotransmitter maintenance (2). NMDARs promote the proliferation and survival of
neuroblasts before synaptogenesis (2). The functions of NMDARs is determined by NR2
subunits (NR2A or NR2B) and NR2 is induced by NRG1. NMDARs main purpose is to stabilize
synapses long term (3). They facilitate signaling pathways involved in neuronal development,
such as learning and memory (2). Early NR2A expression blocks the addition of new spines in
the neuron. Even when NR2B is added later it does not fix the number of synapse formed, that
were significantly decreased due to the early expression of NR2A and its effects on spine
formation. NR2B may contribute to the initiation of synapses, but without it, or with NR2A early
expression, the setup is not prepared, thus fewer spines are formed to make synapses (4).
Erbb4- Mutant mice, mice without the Erbb4 gene, research found that without this gene
early brain development neurons cannot develop properly. For migration to occur NRG1 must be
able to communicate with ErbB, or else neuronal development will stop. The communication
between ErbB and NRG1 provide pattern information for the neurons to follow and enables them
to form in the proper spot at the appropriate time during migration. NRG1 also plays a role in
axon guidance, which allows a single neuron to grow outward rather than in a single direction.
This process also consists of NRG1’s communication with ErbB (4). Specifically the thalamus
cortical axon is dependent on NRG1 and ErbB. These axons are in charge of sending sensory and
motor neurons to the cerebral cortex. Studies have shown that without NRG1 there is no way to
guide the thalamus cortical axon to the cortex. NRG1 has been found to play a major role in the
myelination of neurons. Glial cells, Schwann cells in the PNS and oligodendrocytes in the CNS,
are the cells that actually make the myelin sheath around our neurons. Disrupting NRG1
signaling leads to almost a complete loss of Schwann cells. The purpose of myelin is to speed up
the rate at which cells sends information to their destination (another neuron, muscle, or organ
(2). Without myelination, the Central nervous system and the peripheral nervous system cannot
fire information at a high rate.
Brain derived neurotrophic factor (BDNF) is a mediator of synapse formation. It is a part
of the neurotrophin family and is most active in the hippocampus (involved in learning and
memory), because that is one of the few structures that produces new neurons throughout life.
BDNF binds to TrkB, which is a type of tyrosine kinase that regulates synaptic strength, eliciting
intracellular signaling pathways within the neuron. BDNF enhances NR2B mediated synaptic
transmission by activating TrkB. TrkB form a ligand with BDNF and working together regulate
plasticity. Like NRG1, BDNF also regulates neural development, while NMDARs regulates the
neuronal functions before synaptogenesis. NRG1 works to induce NR2B activation in immature
neurons by using BDNF/TrkB dependent mechanism. This means the TrkB is needed for NRG1
to activate NR2B before synaptogenesis (5). NMDARs are what signal BDNF, so that later they
become the mechanisms that activate NMDAR. Studies show that without NMDAR there is a
decrease in the amount of BDNF, thus a decrease in synapse production (5).
A different protein that has not been discussed is DLG5 MAGUK, and it plays an
important role in dendritic spine formation. The loss of DLG5 leads to a decrease in the number
of spines that are formed in a dendrite and excitatory synapses. MAGUK regulates the
localization of trans- synaptic cell adhesion. In the DLG family however there are PSD95 which
are the subunits that control the localization and trafficking of glutamate receptor through direct
interaction with NMDA. If PSD95 is missing or reduced it could lead to impaired spatial
learning. This is because with decrease number of dendrites there cannot be as many synapses
formed (6).
Neurexins (Nrxn) and neuroligins (Nlgn) are adhesion molecules that connect the
synapse thus allowing neurons to communicate. Nlgn are postsynaptic transmembrane proteins
that are involved in binding the neuron with another neuron by forming a ligand with Neurexins
(5). The Nlgn connect with a Nrxn using an enzyme called cholinesterase. There are four
different types of Nlgn in primates, Nlgn 1 which is commonly used in excitatory synapses.
There is also Nlgn 2 which is generally used in inhibitory synapses, Nlgn 3 which is involved in
both inhibition and excitatory synapses. Then lastly Nlgn 4, this one’s function is unclear, but is
speculated to involve glutamate synapses. Studies have been conducted on knockout (KO) mice,
or mice who have had their DNA engineered to not express a specific gene. In Nlgn KO mice it
has been shown that there are impairments in synaptic transmission. This is because Nlgn must
form a connection with a presynaptic protein, like Nrxn. If the protein has been engineered to not
be expressed in the mouse then the synapses that were supposed to form can no longer form (7).
Some studies have link mutations in these proteins may be a result of autism (8).
Neurexins are a single pass transmembrane presynaptic protein that involves the binding
of two neurons by forming a ligand with Nlgn (8). In mammals there are three different types of
Nrxn genes and each has a different promoter resulting in α (long forms) and β (short form)
Nrxn. When Nrxn and Nlgn interact there is one Nlgn dimer that contacts with two monomeric
Nrxn. Nlgn1 is the gene most likely to interact with Nrxn, which creates an excitatory synapse.
These structures show that there was a presence of Ca2+ which explains the dependency binding
has on Ca2+ . Ca2+ is essential for excitatory synapses to function (7). The interaction between
Nlgn and Nrxn is called trans- synaptic, meaning that a post synaptic protein is interacting with a
pre-synaptic protein. These two proteins working together are the two adhesive molecules that
synapses need to form during synaptogenesis (5). They also deal with both excitatory and
inhibitory synapses. In research done on removing all three α-Nrxn in KO mice it was found that
their synaptic vesicle release was significantly lower than that of normal mice. This is due to the
lack of Nrxn in inhibitory and excitatory synapses. Since Nrxn is involved in excitatory synapses
one can assume that Nrxn may have the ability to interact with GABA. This interaction between
Nrxn and GABA receptors is thought to work in cis (9). Nrxn is also known to communicate
with SynCAMs
As mentioned earlier, Nrxn not only communicate with Nlgn they also interact with
SynCAMs. This protein is present on both post and presynaptic neurons. This protein even
belongs to the same family as Nrxn and Nlgn, the immunoglobulin superfamily and it also
participates in adhesive interactions and contributes to holding Axon and dendrite connection
together; it is an adhesion molecule that directly impacts the number of synapses formed by
altering the shape and growth of the receptors (10). SynCAM is involved in axo-dentritic
interactions, meaning that it is involved in the communication between the axon of one cell and
the dendrites of another. Synaptic adhesion by SynCAM 1 can increase the number of synapses
formed all the while decreasing the plasticity of the neuron. High of this amounts of this protein
allow for more synapses to be made during development. SynCAM is mostly involved in
excitatory synapses in developing and fully developed brains (7). However, more synapses
restrict the amount of plasticity within the synapses and neurons themselves. SynCAM KO mice
showed improved spatial memory. In human, if there is a mutation in SynCAM or Nlgn then that
person will be affected if autism (11).
As one can see synaptogenesis is accomplished through a number of mechanisms that
work together to form the long lasting connections that we have today. Some mechanisms been
around since we were infants. One can also see that if one of these important mechanisms is
mutated or purposely taken out (KO mice) for experimental reason it could have horrendous
effects on the organism. Humans the lack Nrxn are typically diagnosed with autism, which could
lead to future cognitive impairments. Without SynCAM synaptic connections could decrease all
together which would have dastardly effects on one’s cognitive ability. Most individuals who
lack any of these proteins often do not make it out of the embryonic stage. Those that do survive
the embryonic stage and become an infant often times have learning impairments. Missing these
proteins is far more detrimental than an infant losing part of their brain. The plasticity of the
brain is at its highest between one and four meaning that if one hemisphere is removed (often a
procedure for those with epilepsy) they would still be able to function because the neurons
intended for one function can change into neurons intended for a different function. However,
missing these proteins is a potential cause for many mental disabilities (1, 2, and 3)
Works Cited
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