A53T-SNCA Mouse Model

This was determined through a set of experiments. To determine if sodium channel clustering depended on glial cells, hippocampal cells were cultured in the absence of glial cells. This experiment showed that, in the absence of glial cells, Na+ channels were found along the entire length of the axon. They were not concentrated in clusters. Then, another experiment was conducted to determine if the node of Ranvier formation was contact dependent. In this experiment, the dorsal root ganglia were bathed in the extracellular fluid of Schwann cells. Again, nodes of Ranvier did not form. This showed that the node of Ranvier formation mechanism was contact dependent. Another experiment was done to determine if node of Ranvier formation depended on molecular signaling between the Schwann cells and the axon. In this experiment, Schwann cells on a myelinated axon were killed. The nodes of Ranvier disappeared. This showed that molecular signaling played a role in node of Ranvier formation. Eventually, an experiment found that ankyrin G was concentrated at nodes of Ranvier. To determine what proteins interacted with

Increasing extracellular K+ reduces the net diffusion of K+ out of the neuron through the K+ leak channels because the membrane is permeable to K+ ions. Therefore, the K+ ions will diffuse down its concentration gradient from a region of higher concentration to a region of lower concentration.

There is a transient increase in CK2 activity 5 min after high-frequency electrical stimulation during the induction of hippocampal LTP (Charriaut-Marlangue et al. 1991). In addition, brain-derived neurotrophic factor, which is released in an activity-dependent manner and important for synaptic plasticity, activates CK2 in a concentration-dependent manner (Blanquet, 1998).

As previously discussed, the basal ganglia circuit is an important aspect of the pathophysiology of PD. There are five dopamine receptors that are found in the basal ganglia. They are categorized from D1 to D5. D1 and D2 are most significant with relation to the pathophysiology of PD. They are found primarily within motor stratum. These receptors have denervation hypersensitivity due to dopaminergic neuron deficiency. The dopamine producing neurons decrease significantly as the disease process advances, resulting in the depletion of dopamine in the nigrostriatal pathway and the substantia nigra. The subthalamic nucleus is not inhibited due to this hypersensitivity. his can lead to heightened inhibition in the thalamus, causing instability of

Attempts to cure or slow down the progression of Parkinson’s disease have largely failed; researchers in this paper maintain this is obviously a direct result of the lack of insight into the pathogenesis of the disease. Parkinson’s disease is the product of the deaths of a number of dopaminergic (dopamine-secreting) neurons in the substantia nigra pars compacta region (SNc) of the brain. But what causes these deaths? In the paper “‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease,” Chen and researchers find that older neurons in the SNc are unusually reliant on calcium channels and that after blocking these channels, the cells are “rejuvenated” and begin acting like their juvenile counterparts; as a

Dampening serotonergic activity with 5-HT1A can prevent the exocytotic release of dopamine from serotonergic terminals17,26.Though it is thought that DA is released from serotonergic innervations from all the brain areas including the hippocampus, prefrontal cortex, substantia nigraand striatum, the striatum is believed to be responsible for LID because of the source of the major release of DA from L-DOPA from the abundant serotonergic innervation24,25.Therefore, my proposal includes reducing dysregulated serotonergic activity specifically in the striatum with local striatal administration of 5-HT1A agonist in a PD mouse model. Whereas most of the other studies focus on treating dyskinesia with 5-HT1A agonist when LID is already developed in PD17,20,my research proposal will target on the prevention of dyskinesia while giving a L-DOPA treatment for PD. For this purpose, I hypothesize that co-administration of a specific5-HT1Aagonist with L-DOPA may reduce the dysregulation of dopamine and could potentially produce the effectsof L-DOPA treatment for PD without the appearance of

These channels produce a certain kind of electrical current which is known as M - current16. This current is responsible for ensuring that neurons are neither constantly active nor constantly excitable. Therefore, it prevents the occurrence of seizures and brain dysfunction. Once this channel is impaired it results into diminished M - current hence cause multiple neuronal excitations which lead to seizures and brain dysfunction (encephalopathy)9. Although recent studies showed that calmodulin has a role to play as well in regulating KCNQ2 function in seizures17 especially in p.A294V mutation9. The severity of seizures depends on extent of reduction of M - current and distribution of potassium voltage channel9. KCNQ2 gene mutation is acknowledged to cause different kinds of seizures including benign neonatal familial seizures8 which commonly occurs due to p.A294G mutation9 as well as early onset epileptic encephalopathy(EOEE) including infantile spasms and ohtahara syndrome10 which commonly occur due to p.A294V

After observing Madame Schachter’s behavior, it seems as if she is suffering from psychosis. A person suffering from psychosis may hear or see things which are not real. Madame Schachter is experiencing this symptom on page 22 when she says, “Fire! I can see fire! I can see a fire!” In the dark train car, there is no fire and she is simply imagining it. Another symptom of psychosis she undergoes is the difficulty in maintaining her usual level of functioning. On page 22, the novel gives us insight on her normal level of functioning. “...And it was she who worked to support the family.” Now she has psychosis, she can no longer care for her child or herself. The roles have reversed and the son is now trying to care for her. On page 23, “It’s

When looking back on my contributions to my community and society, the thought of me becoming a certified Catholic Youth Organization (CYO) basketball coach comes to mind. After completing an interview along with certification courses, I became the head coach of a 6th grade basketball team at St. Aloysius in Bowling Green, Ohio. I classify this as a contribution to society because I made it my mission to help my players grow as both basketball players and as young men. It was my job to relay the abundance of basketball and life information I had accrued throughout the years. I took this volunteer-based position very seriously due to the importance of basketball in my life. Growing up, I had always been blessed with coaches who put developing young men and their character over anything dealing with basketball. I wanted the practices and games to be more than learning plays and basketball procedures. Rather, I wanted to instill qualities of teamwork, leadership, discipline,

Another study looked at mice hippocampal pyramidal neurons. At higher temperatures the hyperpolarized voltage sodium channels at the AIS contributed to increased excitability. This AIS excitability contributed to increased heat related seizures, which offered that sodium channels play a role in febrile seizures (Wimmer, Reid, Mitchell, Richards, Scaf, Leaw, Petrou, 2010). Another mice oriented study focused on ion channel regulation in the axon initial segment. This study found that dopaminergic signaling can control neuronal output through calcium channels (Bender, Ford, Trussell, 2010).

One recent study attempted to deconstruct the molecular diversity of the midbrain dopamine system. They postulated the existence of several molecularly distinct dopamine neuron subtypes and used a microfluidic dynamic array to simultaneously evaluate the expression of 96 genes in single neurons (Poulin et al., 2014). Using this method identified two main clusters of neurons. They also uncovered 10 genes that appeared to be expressed uniformly in all dopamine neurons (PD linked genes: Atp13a2, Lrrk2, Park2, Park7, and Pink1. Transcription factors: Foxa1, En1/2, Lmx1b, Pitx3, and Nr4a2). Although informative, this study does have some limitations. Firstly the method used restricts the identification of novel subgroups to a combination of only 96 different genes taken from previous gene expression studies. This could have

One of the key ways that membrane proteins are involved in neurone function is through the formation of the resting potential. The resting potential is the charge difference across a cell membrane when a neurone is at rest and not sending a signal, typically between -60 and -80 millivolts. Potassium and Sodium ions play a fundamental role in the formation of the resting potential (Professor Sandidge/Moyle, 2012) and these ions each have a concentration gradient across the membrane of a neuron. In the majority of neurones, the concentration of potassium is greater inside the cell,

It is possible that α-synuclein causes the ER stress by interrupting the vesicular protein trafficking and causing the ER to be overworked. It is also found that mutations in the parkin gene end up forming aggregations of its own substrates in the ER, which leads to stress and death of dopamine neurons (Imai et al., 2001). Other than the stress on the ER created by clusters of incorrectly folded α-synuclein proteins, mitochondria that are functioning improperly can also induce stress on the ER. Parkin is an E3 ubiquitin ligase responsible for regulating many cellular processes by tagging proteins with ubiquitin for their destruction (Dawson and Dawson 2010). A loss of function mutation in the parkin gene is seen to play a major role in altering the function of mitochondria leading to stress on the ER (Bouman et al., 2011). Mutations in PINK1 (PTEN induced putative kinase 1) affect pakin translocation and cause mitochondria to accumulate which increases the vulnerability of dopamine neurons (Song et al., 2013). Along with this, muations in both the parkin gene and PINK1 cause ER stress by increasing contacts between ER and dysfunctional mitochondrial, which can lead to neurodegeneration (Celardo et al., 2016). In rare forms of heredity Parkinson’s disease, mutations in

Despite the various roles for STIM and Orai dependent channels, it is primarily the store-operated channels for which there is information regarding roles in physiological processes. For example, to the author’s knowledge, no publications have appeared utilizing animal models to investigate the importance of ARC channels or SOC channels at the organ system or organism level. Animal models with TRPC channel deletions have revealed numerous physiological functions subtended by these channels, but without experimentally demonstrating that these involve the store-operated activation mode.

Furthermore, dopamine is responsible for keeping cells operating at an appropriate and controlled level. It has a huge role in drug abuse, as it plays a major role in the pleasure and reward system in the brain. The dopaminergic cells decrease or increase the amount of dopamine they produce and are present in one's nervous system. As cocaine penetrates the blood brain barrier, it clogs up dopamine transporters that are designed to move dopamine from the synaptic cleft to inside the cell so that cells do not become overstimulated. However, once cocaine blocks the transporter's, the cocaine binds to dopamine receptors, as shown in the figure above. Thus, cocaine causes the cell to become over stimulated or sensitized. Although, cocaine is inhibitory for the neurotransmitters, norepinephrine, and serotonin. The dopamine system has been important for survival for billions of years. Thus, cocaine alters a fundamental and vital part of the human brain that is crucial to sustaining life.