Marcia H. Ratner

Chronic hypertension with aging induces significant alterations in the structure and function of brain parenchyma and memory dysfunction. While therapeutic control of hypertension reduces risk, the functional changes in neural circuitry that underlie memory deficits are unknown. Identifying possible early onset changes in the hippocampal trisynaptic circuit (HTC) may reveal opportunities for therapeutic intervention. A large-scale clinical study revealed a direct relationship between reduced prospective memory score and reduced hippocampal functional connectivity in subjects with a history of chronic hypertension. Here, we report a potential mechanistic linkage between hypertension/aging and hippocampal neural circuitry dysfunction. We used chronically implanted multi-electrode silicon probes in awake freely behaving rats to monitor synchronous high frequency oscillations (at 140–200 Hz or the “ripple band”) in the HTC CA1 subregion. This hippocampal subregion is known to participate in memory consolidation, in part via HTC ripples. The nootropic drug, α5IA, that inhibits α5GABA-A receptors, was administered orally, under conditions for target engagement, and ripple amplitude measured within subject in awake resting Sprague–Dawley (SD) rats. Significant HTC and memory dysfunction was observed in aged-hypertensive SD rats. The results reveal an hypertension/age-associated anomaly in ripple band activity in SD males, characterized by reductions in mean peak ripple amplitude and in the ability of α5IA to potentiate peak ripple amplitude, without effect upon ripple frequency or duration. Thus, the population of large peak amplitude sharp wave ripples is reduced and becomes insensitive to potentiation by α5IA. Having identified a specific change in peak ripple amplitude that is resistant to potentiation by α5IA, a nootropic probe-drug, this finding could lead to nuanced circuitry level approach for the treatment of memory dysfunction with aging and hypertension.

There is a well-recognized relationship between a person’s body burden of essential trace elements such as copper and their neurological function in which both deficiencies and exposures to excessive concentrations are associated with adverse clinical outcomes. Preclinical studies indicate chronic excess copper exposure is associated with altered motor function, dopaminergic neuronal loss, astrocytosis, and microgliosis. Copper also promotes oligomerization and fibrilization of α-synuclein suggesting it may hasten the course of an α-synucleinopathy. Here we report a rare case of early onset Lewy Body Dementia with Parkinsonism in a 53-year-old Caucasian woman exposed to copper contaminated drinking water for more than 10 years. Her hair and that of her daughter had streaks of blue-green discoloration as did the porcelain sinks in their home. Testing confirmed copper contamination of the drinking water. A neurologist diagnosed her with Lewy Body Dementia with Parkinsonism. Skin biopsy for phosphorylated α was consistent with a diagnosis of an α-synucleinopathy. These findings suggest chronic exposure to excessive copper may act as disease modifying factor in Lewy Body Dementia with Parkinsonism. It has previously been recommended that individuals at risk of Alzheimer’s disease (AD) avoid excessive intake of copper. Genetic studies indicate that Lewy Body Dementia shares risk factors and pathways with AD. Based on the observations in this patient we recommend that individuals at risk for an α-synucleinopathy based on a positive family history, genetic testing, and/or positive results on a skin biopsy for phosphorylated α-synuclein avoid exposure to excess copper.

Hypertension onset with aging is of widespread clinical significance, predominantly in males, yet the neural circuitry underpinnings for hypertension associated memory dysfunction remains unknown. Sprague Dawley (SD) male but not female rats develop age dependent increases in mean arterial blood pressure (MAP) by 16 months of age. We sought to interrogate the functional integrity of the hippocampal trisynaptic circuit (HTC), which is known to participate in memory, to determine whether age-associated increases in MAP contributes to circuitry dysfunction that may lead to mild-cognitive impairment (MCR). Ripples, and specifically sharp-wave ripple oscillations, play a role in memory replay and consolidation during awake immobility among other behaviors. These synchronous high frequency local field potentials (LFPs) in the ripple band (140 to 200 Hz) serve as an HTC level surrogate marker for circuitry function in rodents, non-human primates, and humans. Thus, we asked whether age-associated increased MAP might alter ripple dynamics. Recognizing that each patient responds in a unique way to hypertension we used a within subject design wherein each animal served as its own control in the investigative model. We surgically implanted high density silicon probe electrodes in HTC CA1 of young and aged SD males to determine whether a nootropic drug, α5IA, a negative allosteric modulator of α5 subunit containing type-A GABA receptors, could detect aberrant modulation of ripples within each subject. Here we report that acute oral administration of α5IA selectively modulated ripple amplitude, but not its duration or frequency during epochs of awake immobility. The response of peak ripple amplitude to α5IA is substantially diminished when chronic MAP exceeds 160 mmHg, corresponding to significant hypertension. The results are consistent with a model in which age-associated increases in MAP is associated with dysfunctional α5 GABA-A receptor modulation of ripple amplitude, but not duration or frequency, as a potential precision biomarker for memory dysfunction. Summary: Age-related neurogenic hypertension disrupts memory and ripple band neural circuitry function in the hippocampal trisynaptic circuit involved in memory consolidation.

Adverse effects of drugs on the human nervous system are rarely possible to anticipate based on preclinical neurotoxicity data, thus propagating the centuries long single most important obstacle to drug discovery and development for disorders of the nervous system. An emerging body of evidence indicates that in vivo electrophysiology using chronically implanted high-density electrodes (ciHDE) in freely moving animals is a rigorous method with enhanced potential for use in translational research. In particular, the structure and function of the hippocampal trisynaptic circuit (HTC) is conserved from rodents to primates, including Homo sapiens, suggesting that the effects of therapeutic agents and other potential neurologically active agents, whether beneficial or adverse, are likely to translate across species when interrogated using a conserved neural circuitry platform. This review explores science advances in the rapidly moving field of in vivo ciHDE in animal models of learning and memory. For this reason we focus on the HTC, where substantial research has investigated neural circuitry level responses and specific behaviors that reflect memory permitting a test of the ground truth validity of the findings. Examples of changes in neural network activity induced by endogenous neurotoxicants associated with neurodegenerative diseases, as well as exogenous therapeutics, drugs, and neurotoxicants are presented. Several illustrative examples of relevant findings that involve longer range neural circuitry outside of the HTC are discussed. Lastly, the limitations of in vivo ciHDE as applied to preclinical neurotoxicology are discussed with a view toward leveraging circuitry level actions to enhance our ability to project the specificity of in vitro target engagement with the desired psychopharmacological or neurological outcome. At the same time, the goal of reducing or eliminating significant neurotoxic adverse events in human is the desired endpoint. We believe that this approach will lead to enhanced discovery of high value neuroactive therapeutics that target neural circuitry domains as their primary mechanism of action, thus enhancing their ultimate contribution toward discovery of precision therapeutics.

Decades of research attempting to slow the onset of Alzheimer’s disease (AD) indicates that a better understanding of memory will be key to the discovery of effective therapeutic approaches. Here, we ask whether prodromal neural network dysfunction might occur in the hippocampal trisynaptic circuit by using α5IA as a selective negative modulator of extrasynaptic α5GABA-A receptors in TgF344-AD transgenic rats, a model for early onset AD. The results demonstrate that orally bioavailable α5IA, an established memory enhancer, increases CA1 pyramidal cell mean firing rates and peak CA1 ripple amplitude during wakeful immobility in wild type F344 rats resting in a familiar environment. We show that TgF344-AD rats, which express human amyloid-beta precursor protein (with the Swedish mutation) and human presenilin-1 (with a Δ exon 9 mutation), exhibit high serum Aβ42 and Aβ40 levels by 3 months of age. By 9 months of age, CA1 ripples in young adult TgF344-AD rats are nonresponsive to α5IA indicating network dysfunction prior to the onset of AD pathology and memory dysfunction. These results demonstrate, to the best of our knowledge, the first evidence for prodromal α5GABA-A receptor dysfunction in the AD hippocampal trisynaptic circuit. Moreover, as α5GABA-A receptors are located extrasynaptically and subserve the function of tonic inhibition we posit that an early stage of memory dysfunction involves the disruption of tonic inhibition in the hippocampus.

Parkinsonism and encephalopathy are frequently seen in patients who survive carbon monoxide (CO) poisoning. Neurological findings associated with CO poisoning can emerge immediately after cessation of exposure or following a brief period of pseudo‐recovery. When present, the tremor associated with CO poisoning is typical of the postural/intention type. Here, we report on a rare case of toxic encephalopathy with a dominant‐hand Holmes‐type tremor, characterized by resting, as well as postural and kinetic/intentional components, in a previously healthy 53‐year‐old man exposed to CO while actively engaged in the process of performing a physically demanding skilled labor task. The unique neuropathological and functional changes that give rise to Holmes‐type tremor and how this relates to the selective vulnerability of the inhibitory indirect pathway of the basal ganglia to glutamatergic excitotoxicity mediated by tissue hypoxia are discussed.

Here we report a rare case of reversible neurological symptoms due to chronic ethanol vapor and mist exposure in a 50-year-old machinist who intentionally used undiluted 200 proof ethanol as a cutting fluid while turning metal machine parts on a toolroom lathe for a period of 3 years. Shortly after switching to ethanol as a cutting fluid, the worker began to experience central nervous system symptoms including headaches, fatigue, ataxia, and concentration and memory problems. Clinical neuropsychological assessment revealed mild deficits on tests of attention, executive function, and memory. The worker was subsequently advised to stop using ethanol as a cutting fluid. At follow-up after cessation of exposure the worker reported that his symptoms were remarkably improved.