The ERK1/2 cell signaling pathway is highly conserved and a prominent regulator of processes like cell proliferation, differentiation, and survival. During nervous system development, the ERK1/2 cascade is activated by the binding of growth factors to receptor tyrosine kinases, leading to the sequential phosphorylation of intracellular protein kinases in the pathway and eventually ERK1 and ERK2, the effectors of the pathway. Well-defined germline mutations resulting in hyperactive ERK1/2 signaling have been implicated in a group of neurodevelopmental disorders called RASopathies. RASopathic individuals often display features such as developmental delay, intellectual disability, cardio-facial abnormalities, and motor deficits. In addition, loss-of-function in ERK1/2 can lead to neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability. To better understand the pathology of these neurodevelopmental disorders, the role of ERK1/2 must be examined during the development of specific neuronal and glial subtypes. In this study, we bred transgenic mice with conditional deletion of ERK1/2 in cholinergic neuronal populations to investigate whether ERK1/2 mediates the survival or activity of basal forebrain and striatal cholinergic neurons during postnatal development. By postnatal day 10, we found that ERK1/2 did not seem to mediate cholinergic neuron number within the basal forebrain or striatum. In addition, we showed that expression of FosB, a neuronal activity-dependent transcription factor and target of ERK1/2, was not yet observed in cholinergic neurons within either of these anatomical regions by P10. Finally, our preliminary data suggested that FosB expression within layer IV of the somatosensory cortex, a target domain for basal forebrain cholinergic projections, also did not appear to be mediated by ERK1/2 signaling. However, since cholinergic neuron development is not yet complete by P10, future work should explore whether ERK1/2 plays any role in the long-term survival and function of basal forebrain and striatal cholinergic neurons in adulthood. This will hopefully provide more insight into the pathology of neurodevelopmental disorders and inform future therapeutic strategies.

Alzheimer’s disease (AD) is a devastating disorder that affects the lives of both patients and their loved ones. While it is believed that AD is due to a buildup of amyloid plaques in the brain that eventually lead to the formation of neurofibrillary tangles (NFTs) and result in neurodegeneration, there are many theories that attempt to define the causes of AD. This paper investigates the amyloid and tau theories in more detail, including how these proteins can spread in the brain. It will also take a look into other potential theories that could contribute to AD symptoms such as vascular issues or neuroinflammation. Frontotemporal dementia (FTD) is another form of dementia, albeit much rarer than AD, that is typically characterized by symptoms that follow the opposite progression of AD: behavior and judgement are affected before memory. In addition, FTD is closely related to amyotrophic lateral sclerosis (ALS), a movement disorder that is caused by a loss of motor neurons that results in loss of muscle control. This paper will also examine how FTD and ALS are related, as well as theories behind the potential causes of these disorders. Finally, this paper will examine a patient who exhibits signs and symptoms of both disorders to attempt to determine the potential diagnosis.

Alzheimer’s Disease (AD) is the most prevalent form of dementia and is the sixth leading cause of death in the elderly. Evidence suggests that forms of stress, including prenatal maternal stress (PMS), could exacerbate AD development. To better understand the mechanism linking PMS and AD, we investigated behavior and specific epigenetic markers of the 3xTg-AD mouse model compared to aged-controls in offspring of stressed mothers and non-stressed mothers.

Receptor-interacting serine/threonine protein kinase 1 (RIPK1) is an enzyme whose interaction with tumor necrosis factor receptor 1 (TNFR1) has been found to regulate cell death pathways, such as apoptosis and necroptosis, and neuroinflammation. Accumulating evidence in the past two decades has pointed to increased RIPK1 activity in various degenerative disorders, including Amyotrophic Lateral Sclerosis (ALS), stroke, traumatic brain injury (TBI) and Alzheimer’s Disease (AD). Given the work showing elevated RIPK1 in neurodegenerative disorders, to further understand the role of RIPK1 in disease pathogenesis, we created a conditional mouse overexpressing neuronal RIPK1 on a C57BL/6 background. These conditional transgenic mice overexpress murine RIPK1 under the CAMK2a neuronal promoter and the transgene is under the control of doxycycline. The removal of doxycycline turns on the RIPK1 transgene. Two cohorts of transgenic mice overexpressing neuronal RIPK1 (RIPK1 OE) were produced, and both had doxycycline removed at post-natal day 21. One cohort was behaviorally tested at 3-months-of-age and the second cohort was tested at 9-months-of-age. Behavioral testing included use of the RotaRod and the Morris water maze to assess motor coordination and spatial cognition, respectively. We found that the RIPK1 OE mice showed no deficits in motor coordination at either age but displayed spatial reference learning and memory deficits at 3- and 9-months-of-age. A subset of mice from two independent cohorts were utilized to assess RIPK1 levels and neuronal number. In these two cohorts of mice used for postmortem analysis, we found that at 3 months of age, ~2 months after transgene activation, RIPK1 levels are not higher in the hippocampus or cortex of the RIPK1 OE mice, however at 9 months, ~8 months after transgene activation, RIPK1 levels are significantly higher in the hippocampus and cortex of RIPK1 OE mice compared to the NonTg counterparts. A subset of tissue was stained against the neuronal marker NeuN. Using unbiased stereology to quantify hippocampal CA1 pyramidal neurons, we found no neuronal loss in the 3-month-old RIPK1 OE mice, but a 34.01% reduction in NeuN+ neuron count in 9-month-old RIPK1 OE mice. Collectively our data shows that RIPK1 overexpression impairs spatial reference learning and memory and reduces neuron number in the CA1 of the hippocampus, underlining the potential of RIPK1 as a target for ameliorating CNS pathology.

Stress and stress-related disorders increase the risk of Alzheimer’s Disease (AD) later in life. Some evidence suggests that prenatal maternal stress (PMS) can exacerbate AD. However, the effects of PMS on AD have not been as well studied. Epigenetic changes have been shown to contribute to AD and this is a possible mechanism by which PMS could accelerate AD. Thus, the present study aimed to investigate the effects of PMS on histone modifications, which change gene expression through alterations made to chromatin structure and thereby DNA accessibility. We utilized female 3xTG-AD mice and performed spatial and learning memory assessments between 5 and 6 months of age. Tissue was analyzed for AD pathology and epigenetic markers at 6 months of age were assessed PMS was shown to influence histone modifications H3K4me3 and H3K27me3 in a manner known to promote the expression of genes associated with neurodegeneration. Further, PMS impaired spatial memory, and, interestingly, the data resembled the pattern of H3K4me3 expression across groups, suggesting that this epigenetic modification could modulate the learning and memory effects of PMS. While the presence of hallmark AD pathologies were not accelerated by PMS, PMS did increase early tau phosphorylation events. Thus, this evidence suggests that PMS impairs spatial memory through epigenetic modifications and may potentially exacerbate AD later in life.