Poonam Mathur

Loss of GluN2B-Containing NMDA Receptors in CA1 Hippocampus and Cortex Impairs Long-Term Depression, Reduces Dendritic Spine Density, and Disrupts Learning

NMDA receptors (NMDARs) are key mediators of certain forms of synaptic plasticity and learning. NMDAR complexes are heteromers composed of an obligatory GluN1 subunit and one or more GluN2 (GluN2A–GluN2D) subunits. Different subunits confer distinct physiological and molecular properties to NMDARs, but their contribution to synaptic plasticity and learning in the adult brain remains uncertain. Here, we generated mice lacking GluN2B in pyramidal neurons of cortex and CA1 subregion of hippocampus. We found that hippocampal principal neurons of adult GluN2B mutants had faster decaying NMDAR-mediated EPSCs than nonmutant controls and were insensitive to GluN2B but not NMDAR antagonism. A subsaturating form of hippocampal long-term potentiation (LTP) was impaired in the mutants, whereas a saturating form of LTP was intact. An NMDAR-dependent form of long-term depression (LTD) produced by low-frequency stimulation combined with glutamate transporter inhibition was abolished in the mutants. Additionally, mutants exhibited decreased dendritic spine density in CA1 hippocampal neurons compared with controls. On multiple assays for corticohippocampal-mediated learning and memory (hidden platform Morris water maze, T-maze spontaneous alternation, and pavlovian trace fear conditioning), mutants were impaired. These data further demonstrate the importance of GluN2B for synaptic plasticity in the adult hippocampus and suggest a particularly critical role in LTD, at least the form studied here. The finding that loss of GluN2B was sufficient to cause learning deficits illustrates the contribution of GluN2B-mediated forms of plasticity to memory formation, with implications for elucidating NMDAR-related dysfunction in disease-related cognitive impairment.

Pharmacological or Genetic Inactivation of the Serotonin Transporter Improves Reversal Learning in Mice

Growing evidence supports a major contribution of cortical serotonin (5-hydroxytryptamine, 5-HT) to the modulation of cognitive flexibility and the cognitive inflexibility evident in neuropsychiatric disorders. The precise role of 5-HT and the influence of 5-HT gene variation in mediating this process is not fully understood. Using a touch screen-based operant system, we assessed reversal of a pairwise visual discrimination as an assay for cognitive flexibility. Effects of constitutive genetic or pharmacological inactivation of the 5-HT transporter (5-HTT) on reversal were examined by testing 5-HTT null mice and chronic fluoxetine-treated C57BL/6J mice, respectively. Effects of constitutive genetic loss or acute pharmacological depletion of 5-HT were assessed by testing Pet-1 null mice and para-chlorophenylalanine (PCPA)-treated C57BL/6J mice, respectively. Fluoxetine-treated C57BL/6J mice made fewer errors than controls during the early phase of reversal when perseverative behavior is relatively high. 5-HTT null mice made fewer errors than controls in completing the reversal task. However, reversal in Pet-1 null and PCPA-treated C57BL/6J mice was not different from controls. These data further support an important role for 5-HT in modulating reversal learning and provide novel evidence that inactivating the 5-HTT improves this process. These findings could have important implications for understanding and treating cognitive inflexibility in neuropsychiatric disease.

Genetic relationship between anxiety-related and fear-related behaviors in BXD recombinant inbred mice.

Mood and anxiety disorders, and rodent phenotypic measures modeling these disorders, have a strong genetic component. Various assays are used to study the neurobiological basis of fear-related and anxiety-related behaviors, phenotype genetically modified mice, and elucidate pharmacological modulation of these behaviors for medication development. Earlier work, however, suggests that different trait measures are mediated by partly overlapping but ultimately distinct genetic factors. In this study, we assessed a novel panel of 23 C57BL/6J×DBA/2J (BXD) recombinant inbred strains on various trait measures of Pavlovian fear conditioning and anxiety-like behavior (novel open field, elevated plus-maze), as well as sensory (acoustic startle, prepulse inhibition of startle) and motor (baseline coordination and learning on accelerating rotarod) function. Results showed that traits were continuously distributed across strains and had modest to strong R2 values. Principal components analysis resolved the data into five factors: factor 1 loaded fear-related traits, factor 2 loaded elevated plus-maze measures as well as context fear, factor 3 loaded novel open field measures and plus-maze closed arm entries, factor 4 loaded rotarod motor function, and factor 5 loaded acoustic startle and prepulse inhibition. These data add to evidence that murine measures of fear-like and anxiety-like traits reflect distinct constructs mediated by dissociable gene variants.

Fear memory impairing effects of systemic treatment with the NMDA NR2B subunit antagonist, Ro 25-6981, in mice: Attenuation with ageing

N-methyl-D-aspartate receptors (NMDARs) are mediators of synaptic plasticity and learning and are implicated in the pathophysiology of neuropsychiatric disease and age-related cognitive dysfunction. NMDARs are heteromers, but the relative contribution of specific subunits to NMDAR-mediated learning is not fully understood. We characterized pre-conditioning systemic treatment of the NR2B subunit-selective antagonist Ro 25-6981 for effects on multi-trial, one-trial and low-shock Pavlovian fear conditioning in C57BL/6J mice. Ro 25-6981 was also profiled for effects on novel open field exploration, elevated plus-maze anxiety-like behavior, startle reactivity, prepulse inhibition of startle, and nociception. Three-month (adult) and 12-month old C57BL/6Tac mice were compared for Ro 25-6981 effects on multi-trial fear conditioning, and corticolimbic NR2B protein levels. Ro 25-6981 moderately impaired fear learning in the multi-trial and one-trial (but not low-shock) conditioning paradigms, but did not affect exploratory or anxiety-related behaviors or sensory functions. Memory impairing effects of Ro 25-6981 were absent in 12-month old mice, although NR2B protein levels were not significantly altered. Present data provide further evidence of the memory impairing effects of selective blockade of NR2B-containing NMDARs, and show loss of these effects with ageing. This work could ultimately have implications for elucidating the pathophysiology of learning dysfunction in neuropsychiatric disorders and ageing.

Giant Primary Retroperitoneal Teratoma in an Adult: A Case Report

Teratomas are bizarre neoplasms derived from embryonic tissues that are typically found only in the gonadal and sacrococcygeal regions of adults. Retroperitoneal teratomas are rare and present challenging management options. We report here the case of a histologically unusual retroperitoneal tumor detected on computed tomography during the workup of abdominal pain in a 32-year-old male. The evaluation and treatment of this condition and a review of the literature are included in this paper.

The intricate relationship of histoplasmosis and sarcoidosis: a case report

IntroductionHistoplasmosis is an endemic mycosis with most cases of clinical illness reported in North and Central America. Rarely, patients develop progressive disseminated histoplasmosis with extrapulmonary manifestations. These infections are fatal if not appropriately treated.Case presentationWe report a case of progressive disseminated histoplasmosis presenting with fever, progressive dyspnea, and pancytopenia in a 51-year-old Caucasian man who had been treated with chronic steroids for a diagnosis of sarcoidosis made 20 years previously. His presentation was initially mistaken for sarcoidosis but, fortunately, laboratory results showed hematologic abnormalities, and the diagnosis of histoplasmosis was made by bone marrow biopsy.ConclusionsSarcoidosis reduces T cell activity, and the addition of steroids for treatment causes further immunosuppression and vulnerability for development of a disseminated infection. The diagnosis of histoplasmosis depends mainly on clinical presentation and host factors. Although there are diagnostic laboratory tests available, clinicians may need to diagnose histoplasmosis by history and physical examination alone and treat empirically, since awaiting Histoplasma-specific laboratory results would delay initiation of treatment. Primary care providers, hospitalists, and subspecialists alike should be aware of the overlap in clinical and radiological presentations of sarcoidosis and histoplasmosis, and when and how to pursue diagnostic testing for endemic mycoses, since these infections can be fatal in immunosuppressed patients without appropriate treatment.

Treatment of hepatitis C in renal impairment and renal transplant

Opinion statementChronic hepatitis C infection is a major cause of morbidity and mortality in the USA. Treatment options have progressed from interferon-based regimens with moderate efficacy and many adverse effects to the use of directly-acting antiviral agents that are highly efficacious with limited side effect profiles. There is a disproportionate number of patients with end-stage renal disease who are infected with hepatitis C and have an increased risk of cirrhosis and hepatocellular carcinoma, while suffering from a lower quality of life. Renal transplant patients with hepatitis C additionally have an increased risk of graft failure, so treatment is of utmost importance in this population. There are currently several options for hepatitis C treatment in the renal impairment and transplant populations which have similar efficacy compared to the general population; however, the safety of these regimens is still being ascertained. Paritaprevir/ritonavir/ombitasvir and dasabuvir or elbasvir/grazoprevir are good options for use in patients with severe renal impairment or post-renal transplant; however, close monitoring is important given the potential for drug-drug interactions and the need for ribavirin in some of these patients. Several limited recent studies suggest that the efficacy and safety of full doses of sofosbuvir in these populations is not significantly different compared to that in the general population, though the safety of this dosing has not yet been established. Treatment of chronic hepatitis C infection in patients with renal impairment and/or transplant can significantly reduce the morbidity and mortality from cirrhosis and hepatocellular carcinoma, while serving as an effective public health tool to reduce transmission.

644Rising Incidence of Syphilis Among Rural HIV+ Men Despite Systematic, Point of Care Prevention Counseling

644. Rising Incidence of Syphilis Among Rural HIV+ Men Despite Systematic, Point of Care Prevention Counseling Poonam Mathur, MD; John Zurlo, MD; Patsi Albright, CRNP, PhD; Tonya Crook, MD; Cynthia Whitener, MD; Ping Du, MD, PhD; Medicine, Hershey Medical Center, Hershey, PA; Medicine/Infectious Diseases, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA; Medicine/Public Health Sciences, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA