N-Disc1 Transgenic Mouse Model

Genetic mutations seen in people with schizophrenia may lead to abnormal brain development and neurotransmission. For example, mutations in NRG1, a gene located on chromosome 8, have been implicated in schizophrenia. This gene codes for a growth factor that is involved in neuronal development and differentiation as well as regulation of postsynaptic density. Additionally, DISC1, located on chromosome 1 at a balanced translocation breakpoint, is associated with schizophrenia. The protein coded for by DISC1 plays a role in both neuronal development and adult brain function through effects on the neurite architecture, migration of neurons, synaptic transmission, and intracellular transport. The DISC1 protein also interacts with phosphodiesterase 4B, resulting in the inactivation of cAMP, which has been reported to play a role in mood, memory and learning. Furthermore, RGS4, a gene located on chromosome 1, has been implicated in neuronal differentiation and studies have shown that brain tissue of schizophrenic patients show reduced expression of the RGS4 protein (DNA Learning Center). Scientists believe that the differences in neuronal distribution seen in schizophrenia patients occur prenatally and that these changes may result in the formation of impaired connections in the brain. In addition, imbalances in the

“There is evidence that PME directly affects the development of the central nervous system (CNS) in both animals and humans” (Day, Goldschmidt & Thomas, 2006).

Had primate models to determine how the change in dopamine levels was related to mental disorders.

Depression comes in all kinds of forms including, Major depression, Clinical depression, and Major depressive disorder. There are multiple different contributors to what causes it. Many scientists and doctors have found that “scans showed patients with clinical depression had less brain volume in several regions, including the frontal lobe, basal ganglia and hippocampus.” (Nordquist) An article published in “Harvard Health Publications” explained that although there aren’t just one chemical that is too high or too low, there are several that are playing a large role in depression disorders. As chemical and biological factors are at play, some disorders like bipolar disorder, schizophrenia autism, major depressive disorder, and attention-deficit hyperactivity disorder share genes that can only be inherited. Depression can have multiple symptoms, suicidal tendencies, self injury, self hating, hopelessness and individuals can become restless and develope sleeping disorders like

The sociodevelopmental-cognitive model displays the interaction between the dopamine system and environmental risk factors (Howes & Murray, 2014). Individuals who develop schizophrenia tend to show excessive increases in dopamine levels during psychosis. The link between dopaminergic alterations and neurodevelopment damage has become more evident and underlies psychosis (Howes & Murray, 2014). The model insinuates interventions to interrupt dysregulations in dopamine by alleviating stressors and incorporating cognitive

During normal development of the mammalian central nervous system (CNS), neural stem cells (NSC) give rise to neurons via process of neurogenesis (Kempermann et al., 2004; Zhao et al., 2008). Neurogenesis normally occurs in dentate gyrus (DG) region of the hippocampus and lateral ventricle of sub-ventricular zone (SVZ) (Zhao et al., 2008). Hippocampal neurogenesis plays pivotal role in neurologic and psychiatric disorder like epilepsy, depression, schizophrenia and mood disorders (Antonova et al., 2004; Keller and Roberts, 2008; Lucassen et al., 2006; Zhao et al., 2008). Development of the nervous system is complex, and includes multistep dynamic processes such as proliferation, differentiation, migration, expansion of axons and dendrites, synapse formation, myelination and programmed cell death (Rice and Barone, 2000). These processes required the coordinated expression of cellular and molecular events in a spatial and temporal manner during the brain development (Rice and Barone, 2000; Rodier, 1994). Several growth factors and signal transduction cascades have been implicated in controlling NSC behavior in the developing brain (Faigle and Song, 2013). Among these, members of the Wnt family of secreted glycoprotein thought to be variably influence proliferation and lineage decisions of NSC and their progeny (Clevers et al., 2014).

Fragile X Syndrome is a genetic disorder caused by a disruption in the FMR1 gene and is the most recurrent inherited form of intellectual disability (Bagni, et al., 2012). It can cause a variety of mental effects ("Fragile X syndrome", 2017). For these reasons, Fragile X Syndrome has the chance of being a model of translational neuroscience (Jayaseelan, Tenenbaum, 2012).

Although many studies have shown that impaired neurotransmission of serotonergic and dopaminergic pathways are related to depression [2], the pathophysiology of depression is yet to be fully elucidated [3]. Several studies are being conducted to unravel the underlying mechanism in evaluating the therapeutic efficacy of antidepressants [4,5]. More so, chronic stress exposure has been found to cause atrophy of neurons in rodent hippocampus. [6,7] As such, decreased hippocampal plasticity might be closely connected to depression. Recent studies have found that administration of antidepressant agents to either stress-induced models or patients could heighten developed neurons in the hippocampus, which in turn attenuates the depression symptoms [8,9]. Researches have demonstrated that the expression of SYP is reduced in brain of depressed patients, suggesting a correlation to the pathophysiology of depression [10,11]. Brain magnetic resonance imaging shows that hippocampal volume is significantly smaller in patients with depression compared with normal control [12]. In vitro experiments have also established that depression ensues along with high levels of cell apoptosis as well as increased protein level of Beclin 1 and LC3 [13, 14]. Thus, apoptosis and autophagy

p. 188). Although studies show that it is not always the case that BD is directly inherited from parents, there is a higher chance of mood disorders in the offspring of BD parents. Studies have shown that the environment and stress can cause “changes in gene expression during key developmental periods” (Pishva, 2014. p. 341). These stressors can affect individuals either through the parent during utero (while a baby is developing) or during their lifetime, as an adult. Environmental exposures during early postnatal life have been associated with mental disorders, including bipolar disorder. One example is maternal care. There is an association of maternal care and “hippocampus-related learning and memory processes” (Pishva, 2014. P. 341). The author asserts that environmental influences affect gene expression and behavior. There are many genes and proteins which are interdependent on each other, and if one is affected due to an environmental factor, it affects the other, increasing levels of stress regulator systems, which affect the behaviors of individuals (Pishva, 2014. p. 342). Environmental factors including drug use are also related with BD. This is not to say that the use of drugs can cause BD or other mood disorders, however, the presence of certain disorders and the use of drugs are sometimes connected. For instance, use of methamphetamine is associated with altered expression of major DNA enzyme DNMTI,

According to a study by the National Institute of Health (NIH), “children with ADHD who had the z-repeat version of the dopamine D4 receptor gene had thinner-than normal areas in the brain’s out mantle, the cerebral cortex” (Teens with ADHD 2). Meaning that children with ADHD who were constantly being tested were all seen having the same gene variation in their brains. Thus showing that within ADHD it causes a type of gene to be thinner than it is supposed to be causing a malfunction in the brain’s production of chemicals. After experimenting with children with ADHD throughout their childhood the NIH concluded that ADHD, “Likely stems from interactions between several genes and non-genetic genes” (Teens with ADHD 2). This proves that ADHD not only is caused by the variation of genes but also of several other factors. Furthermore, proving that the variation of genes is one of the reason and ways that ADHD could be proven by doctors and

According to Gonen-Yaacovi, Attention Deficit Hyperactivity Disorder (ADHD) is an illness in which an individual suffers from frequent difficulty in attention retention and thus experiences impulsivity and hyperactivity (Gonen-Yaacovi et al, 50). One major behavioral symptom of ADHD is “increased reaction time variability,” which has been found in studies of cognitive tasks involving stop-signal, maintained attention to stimuli, choice reaction time (CRT), and “go-no-go” (Gonen-Yaacovi et al., 50-51). This inhibition to reaction negatively impacts a person’s ability to maintain an attention-span, have a full-functioning memory, switch tasks, and fully control motor skills (Gonen-Yaacovi et al., 51). The prevalence of ADHD has increased in the past decade (Nigg, 524), and studies have shown that ADHD affects about 5% of children, with symptoms persisting into adolescence in as many as 65% of studied individuals (Friedman and Rapoport, 106). The etiology of ADHD has been studied for many decades, and the disorder has been linked to genetic markers such as DAT1, DRD4, DRD5, 5HTT, HTR1B, and SNAP25, and environmental factors (Nigg, 525). The culmination of these risk factors has contributed to ADHD’s association with emerging changes in early brain development.

It affects 40 million adults in America that are eighteen and older, which is 18% of the population. People suffering with anxiety disorder of some kind are three to five times more likely to go to the doctor and six times more likely to be hospitalized for psychiatric reasons. With all types of anxiety women are twice as likely to be affected as men. Also, Anxiety disorder cost the U.S more than 42 million dollars a year, which is almost one-third of the country’s 148 million dollar total mental health bill. However, more research is coming to light. Recently a team of Montreal researchers at the IRCM discovered that the protein PC7 plays a crucial role in the brain by causing certain types of cognitive performance like anxiety. The researchers also found that a lack of PC7 in the brain can also result in an excess of dopamine in the brain. The team tested this new approach by modifying a drug that is used against Alzheimer’s disease in order to block the action of dopamine in the brain. The team tested the effects of this new drug on mice that were lacking PC7, they found that it was a success in reducing the levels of dopamine in the brain. The team of researchers believe that the drug could increase the levels of dopamine in the bran, which would then normalize the brains reaction to cause

Abnormal metabolite levels across major WM pathways suggested abnormal transmission of information in patients with DD. Abnormal neurotransmission, in turn, would lead to abnormal integration and processing of information in gray matter. Metabolite levels were abnormal in several GM regions that support emotional and cognitive processes. In particular, patients had abnormal levels in (a) the insula, which supports subjective emotional experience, emotional processing51, empathy, and social decision making52; and (b) the caudate and putamen, which in addition to regulating planning53 and sequencing54 of fine motor tasks55,56, regulate working memory focus57, motivation, and reward perception58,59. Thus, our findings indicate possible neuroanatomic substrata for disrupted cognitive-emotional processing in patients with DD.

Histone modifications have a very crucial role when it comes to silencing genes through chromatin remodeling. Changes in histone modifications can highly disrupt neuronal functions, along with inhibitions to the gene, BDNF (Brain-derived neurotrophic factor), which is crucial for cognition, learning, memory formation, and vulnerability to social life and experiences. Mutations in this gene are associated with susceptibility to Schizophrenia. Increased inhibition of this gene has a positive correlation with methylated CpG sites. Currently, anti-depressants keep receptors active. I will try to develop a method that would perhaps uninhibit the down-regulation of BDNF.

This further shows how this gene and this particular allele is considered one of the strongly associated candidates in ADHD. The dopamine transporter DAT1 is generally expressed in striatal regions, a set of brain regions that have been shown to have an increased binding of DAT associated with the presence of the 9R allele (van der Meer et al., 2017).