Postdoctoral fellow , Columbia University
I aim to identify the neural ensembles linking anxiety and AD by utilizing optogenetics and imaging.
Alzheimer’s disease (AD), which affects more than 5 million individuals, is a progressive and debilitating neurodegenerative and psychiatric disorder that cannot be reversed or halted. Like many mental disorders, AD is characterized by the inability to function daily, engage in relationships, and participate in activities. Although many studies examining cerebrospinal fluid and neuroimaging biomarkers have shown promise as new diagnostic criteria for predicting those at risk for AD, the clinical diagnosis is still largely based on cognitive decline. These data suggest that there are other variables at play. Neuropsychiatric disturbances, such as depression and anxiety, are observed in 90% of AD patients and are frequent in those at risk for AD. However, much of the field has been focused on depression until recent reports found controversial evidence regarding the relationship between anxiety and AD. Clinical evidence supports that anxiety symptoms predict the conversion to AD, over and beyond the effects of depression, memory loss, and even atrophy. Although most AD studies have been performed using male mice, recent evidence suggests that females are more susceptible to depression, anxiety, and AD when compared to males. In fact, two-thirds of AD patients are women. Here, I aim to identify the neural ensembles linking anxiety and AD by utilizing behavioral studies, optogenetics, whole-brain microscopy, and in vivo Ca2+ imaging in female mice. Results from this project will provide the building blocks for specific and personalized therapeutic targets for females suffering from AD.
Abstract: Peripheral infections increase the propensity and severity of seizures in susceptible populations. We have previously shown that intraperitoneal (i.p.) injection of a viral mimic, polyinosinic-polycytidylic acid (PIC), elicits hypersusceptibility of mice to kainic acid (KA)-induced seizures. The present study was undertaken to determine whether this seizure hypersusceptibility entails alterations in glutamate signaling. Female C57BL/6 mice were i.p. injected with PIC, and after 24 hours, glutamate homeostasis in the hippocampus was monitored using the enzyme-based microelectrode arrays. PIC challenge robustly increased the level of resting extracellular glutamate. While presynaptic potassium-evoked glutamate release was not affected, glutamate uptake was profoundly impaired and non-vesicular glutamate release was augmented, indicating functional alterations of astrocytes. Electrophysiological examination of hippocampal slices from PIC-challenged mice revealed a several fold increase in the basal synaptic transmission as compared to control slices. PIC challenge also increased the probability of presynaptic glutamate release as seen from a reduction of paired-pulse facilitation (PPF) and synaptic plasticity as seen from an enhancement of long-term potentiation (LTP). Altogether, our results implicate a dysregulation of astrocytic glutamate metabolism and an alteration of excitatory synaptic transmission as the underlying mechanism for the development of hippocampal hyperexcitability, and consequently seizure hypersusceptibility following peripheral PIC challenge. This article is protected by copyright. All rights reserved.
Pub.: 12 May '16, Pinned: 25 Aug '17
Abstract: Peripheral viral infections increase seizure propensity and intensity in susceptible individuals. We have modeled this comorbidity by demonstrating that the acute phase response (APR) instigated by an intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC), induces protracted hypersusceptibility to kainic-acid (KA)-induced seizures. We have further demonstrated that PIC challenge robustly increases the level of tonic extracellular glutamate and neuronal excitability in the hippocampus. The present study was undertaken to determine a relationship between tonic glutamate and seizure susceptibility following PIC challenge. Briefly, glutamate-sensing microelectrodes were permanently implanted into the CA1 of eight-week old female C57BL/6 mice. Following a three day recovery, APR was induced by i.p. injection of 12 mg/kg of PIC, while saline-injected mice served as controls. Tonic glutamate was measured at 1, 2, 3 and 4 days after PIC challenge. PIC challenge induced an approximately 4-fold increase in tonic glutamate levels measured after 24 h. The levels gradually declined to the baseline values within four days. 24 h after PIC challenge, the mice featured an approximately 3-fold increase in cumulative seizure scores and 2-fold increase in the duration of status epilepticus induced by subcutaneous (s.c.) injection of 12 mg/kg of KA. Seizure scores positively correlated with pre-seizure tonic glutamate. Moreover, seizures resulted in a profound (76%) elevation of extracellular glutamate in the CA1 of PIC-challenged but not saline-injected mice. Our results implicate the increase of extracellular glutamate as a mediator of seizure hypersusceptibility induced by peripheral viral challenge. This article is protected by copyright. All rights reserved.
Pub.: 01 Mar '17, Pinned: 25 Aug '17
Abstract: Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus, cornu ammonis 3 (CA3), and cornu ammonis 1 (CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter 1, which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1, the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD.
Pub.: 07 Jul '15, Pinned: 17 Aug '17
Abstract: Individuals at risk of developing Alzheimer's disease (AD) often exhibit hippocampal hyperexcitability. A growing body of evidence suggests that perturbations in the glutamatergic tripartite synapse may underlie this hyperexcitability. Here, we used a tau mouse model of AD (rTg(TauP301L)4510) to examine the effects of tau pathology on hippocampal glutamate regulation. We found a 40% increase in hippocampal vesicular glutamate transporter, which packages glutamate into vesicles, and has previously been shown to influence glutamate release, and a 40% decrease in hippocampal glutamate transporter 1, the major glutamate transporter responsible for removing glutamate from the extracellular space. To determine whether these alterations affected glutamate regulation in vivo, we measured tonic glutamate levels, potassium-evoked glutamate release, and glutamate uptake/clearance in the dentate gyrus, cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. P301L tau expression resulted in a 4- and 7-fold increase in potassium-evoked glutamate release in the dentate gyrus and CA3, respectively, and significantly decreased glutamate clearance in all three regions. Both release and clearance correlated with memory performance in the hippocampal-dependent Barnes maze task. Alterations in mice expressing P301L were observed at a time when tau pathology was subtle and before readily detectable neuron loss. These data suggest novel mechanisms by which tau may mediate hyperexcitability. Pre-synaptic vesicular glutamate transporters (vGLUTs) package glutamate into vesicles before exocytosis into the synaptic cleft. Once in the extracellular space, glutamate acts on glutamate receptors. Glutamate is removed from the extracellular space by excitatory amino acid transporters, including GLT-1, predominantly localized to glia. P301L tau expression increases vGLUT expression and glutamate release, while also decreasing GLT-1 expression and glutamate clearance.
Pub.: 17 Oct '14, Pinned: 17 Aug '17
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