Samantha L. Hodges

Spectral and temporal properties of calls reveal deficits in ultrasonic vocalizations of adult Fmr1 knockout mice

&NA; The Fmr1 knockout (KO) mouse has commonly been used to investigate communication impairments, one of the key diagnostic symptoms observed in Fragile X syndrome (FXS) and Autism spectrum disorder (ASD). Many studies have found alterations in ultrasonic vocalizations (USVs) in neonatal Fmr1 KO mice, however, there is limited research investigating whether these deficits continue into adulthood. In the present study, we examine differences in female urine‐induced ultrasonic vocalizations, scent marking behavior, odor discrimination, and open field activity in adult male Fmr1 KO and wildtype (WT) mice. Overall, we found extensive alterations between genotypes in both spectral and temporal properties of ultrasonic vocalizations. There was no difference in the average number of calls emitted by both genotypes, however, Fmr1 KO mice emitted calls of a higher frequency, decreased amplitude, and shorter duration than WT mice. Spectrographic analyses revealed statistically significant differences between genotypes in the types of calls emitted. Contrastingly, we found no differences in scent marking behavior, a form of social communication, or in odor discrimination and activity levels of the mice. The results corroborate previous studies emphasizing the importance of qualitative differences observed in vocalization behavior of Fmr1 KO mice, rather than quantitative measurements such as number of calls emitted. Overall, the study confirms the presence of abnormalities in vocalization behavior in adult Fmr1 KO mice that we believe are consistent with communication deficits seen in the syndrome. HighlightsNo difference in average quantity of calls produced between Fmr1 KO and WT mice.Fmr1 KO mice emit vocalizations at a higher frequency and decreased amplitude.Fmr1 KO vocalizations were of significantly shorter duration.Spectral analysis reveal Fmr1 KO mice to produce different types of calls.Results emphasize qualitative differences in Fmr1 KO mice vocalizations.

Neuropsychological findings associated with Panayiotopoulos syndrome in three children

Panayiotopoulos syndrome is a common idiopathic benign epilepsy that has a peak age of onset in early childhood. The syndrome is multifocal and shows significant electroencephalogram (EEG) variability, with occipital predominance. Although a benign syndrome often refers to the absence of neurological and neuropsychological deficits, the syndrome has recently been associated with cognitive impairments. Also, despite frequent occipital EEG abnormalities, research regarding the visual functioning of patients is less reported and often contradictory. The purpose of this study was to gain additional knowledge regarding the neurocognitive functioning of patients with Panayiotopoulos syndrome and specifically to address any visual processing deficits associated with the syndrome. Following diagnosis of the syndrome based on typical clinical and electrophysiological criteria, three patients, aged 5, 8, and 10years were referred by epileptologists for neuropsychological evaluation. Neuropsychological findings suggest that the patients had notable impairments on visual memory tasks, especially in comparison with verbal memory. Further, they demonstrated increased difficulty on picture memory suggesting difficulty retaining information from a crowded visual field. Two of the three patients showed weakness in visual processing speed, which may account for weaker retention of complex visual stimuli. Abilities involving attention were normal for all patients, suggesting that inattention is not responsible for these visual deficits. Academically, the patients were weak in numerical operations and spelling, which both rely partially on visual memory and may affect achievement in these areas. Overall, the results suggest that patients with Panayiotopoulos syndrome may have visual processing and visual memory problems that could potentially affect their academic capabilities. Identifying such difficulties may be helpful in creating educational and remedial assistance programs for children with this syndrome, as well as developing appropriate presentation of information to these children in school.

Wnt/β-catenin signaling as a potential target for novel epilepsy therapies

Epilepsy is one of the most common neurological disorders, and yet many afflicted individuals are resistant to all available therapeutic treatments. Existing pharmaceutical treatments function primarily to reduce hyperexcitability and prevent seizures, but fail to influence the underlying pathophysiology of the disorder. Recently, research efforts have focused on identifying alternative mechanistic targets for anti-epileptogenic therapies that can prevent the development of chronic epilepsy. The Wnt/β-catenin pathway, one possible target, has been demonstrated to be disrupted in both acute and chronic phases of epilepsy. Wnt/β-catenin signaling can regulate many seizure-induced changes in the brain, including neurogenesis and neuronal death, as well as can influence seizure susceptibility and potentially the development of chronic epilepsy. Several genome-wide studies and in vivo knockout animal models have provided evidence for an association between disrupted Wnt/β-catenin signaling and epilepsy. Furthermore, approved pharmaceutical drugs and other small molecule compounds that target components of the β-catenin destruction complex or antagonize endogenous inhibitors of the pathway have shown to be protective following seizures. However, additional studies are needed to determine the optimal time period in which modulation of the pathway may be most beneficial. Overall, disrupted molecular networks such as Wnt/β-catenin signaling, could be a promising anti-epileptogenic target for future epilepsy therapies.

A single seizure selectively impairs hippocampal-dependent memory and is associated with alterations in PI3K/Akt/mTOR and FMRP signaling

A single brief seizure before learning leads to spatial and contextual memory impairment in rodents without chronic epilepsy. These results suggest that memory can be impacted by seizure activity in the absence of epilepsy pathology. In this study, we investigated the types of memory affected by a seizure and the time course of impairment. We also examined alterations to mammalian target of rapamycin (mTOR) and fragile X mental retardation protein (FMRP) signaling, which modulate elements of the synapse and may underlie impairment.

Neuronal subset-specific deletion of Pten results in aberrant Wnt signaling and memory impairments

The canonical Wnt and PI3K/Akt/mTOR pathways both play critical roles in brain development early in life. There is extensive evidence of how each pathway is involved in neuronal and synaptic maturation, however, how these molecular networks interact requires further investigation. The present study examines the effect of neuronal subset-specific deletion of phosphatase and tensin homolog (Pten) in mice on Wnt signaling protein levels and associated cognitive impairments. PTEN functions as a negative regulator of the PI3K/Akt/mTOR pathway, and mutations in Pten can result in cognitive and behavioral impairments. We found that deletion of Pten resulted in elevated Dvl2, Wnt5a/b, and Naked2, along with decreased GSK3β hippocampal synaptosome protein expression compared to wild type mice. Aberrations in the canonical Wnt pathway were associated with learning and memory deficits in Pten knockout mice, specifically in novel object recognition and the Lashley maze. This study demonstrates that deletion of Pten not only significantly impacts PI3K/Akt/mTOR signaling, but affects proper functioning of the Wnt signaling pathway. Overall, these findings will help elucidate how the PI3K/Akt/mTOR pathway intersects with Wnt signaling to result in cognitive impairments, specifically in memory.

The α5-GABA A R inverse agonist MRK-016 upregulates hippocampal BDNF expression and prevents cognitive deficits in LPS-treated mice, despite elevations in hippocampal Aβ

HighlightsRepeated peripheral LPS administration increases expression of central A&bgr;.Administration of MRK‐016 post‐training rescues memory consolidation following LPS administration.MRK‐016‐treated animals showed BDNF mRNA expression comparable to control animals.Repeated injections of LPS and increased A&bgr; expression are congruent with downregulation of TrkB.Nurr1 expression is reduced following repeated LPS treatment, but is increased following behavioral training. Abstract Alzheimer’s disease is marked by the presence of amyloid‐beta (A&bgr;) plaques, elevated central cytokine levels, dysregulation of BDNF‐related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central A&bgr; in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK‐016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS‐induced hippocampal A&bgr; accumulation. Hippocampal A&bgr; was significantly elevated, relative to saline‐treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal A&bgr;, and inhibit acquisition of contextual fear. Post‐training treatment with MRK restored behavioral expression of fear in LPS‐treated animals, despite elevated hippocampal A&bgr;, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS‐ induced cognitive deficits associated with elevated A&bgr;, and restore hippocampal BDNF expression.

Adult Fmr1 knockout mice present with deficiencies in hippocampal interleukin-6 and tumor necrosis factor-α expression

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a single genetic mutation in the FMR1 gene. Mutations in the FMR1 gene are the largest monogenic cause of autism spectrum disorder (ASD), and thus both disorders share many of the same cognitive and behavioral impairments. There is increasing evidence suggesting that dysregulated immune responses play a role in the pathophysiology of ASD; however, the association between FXS and altered immunity requires further investigation. This study examined whether Fmr1 knockout (KO) and wild-type mice on a FVB/NJ background strain had altered cytokine expression at baseline levels in the hippocampus. Results showed Fmr1 KO mice to have decreased proinflammatory cytokine hippocampal mRNA expression, specifically interleukin (IL)-6 and tumor necrosis factor-&agr;, compared with wild-type mice. However, no differences were detected in the expression levels of IL-1&bgr;, MCP-1, interferon-&ggr;, or IL-10. Despite the high comorbidity between FXS and ASD, these results suggest that the Fmr1 KO mouse does not mimic the increased proinflammatory cytokine expression commonly found in ASD mouse models and patients. Further investigation of the immune profile of the Fmr1 KO mouse is critical to understand whether this deficiency of cytokines in the hippocampus is indicative of a broader immunologic deficit associated with FXS.

Early-life status epilepticus acutely impacts select quantitative and qualitative features of neonatal vocalization behavior: Spectrographic and temporal characterizations in C57BL/6 mice

Early-life seizures are known to cause long-term deficits in social behavior, learning, and memory, however little is known regarding their acute impact. Ultrasonic vocalization (USV) recordings have been developed as a tool for investigating early communicative deficits in mice. Previous investigation from our lab found that postnatal day (PD) 10 seizures cause male-specific suppression of 50-kHz USVs on PD12 in 129 SvEvTac mouse pups. The present study extends these findings by spectrographic characterization of USVs following neonatal seizures. On PD10, male C57BL/6 pups were administered intraperitoneal injections of kainic acid or physiological saline. On PD12, isolation-induced recordings were captured using a broad-spectrum ultrasonic microphone. Status epilepticus significantly suppressed USV quantity (p=0.001) and total duration (p<0.05). Seizure pups also utilized fewer complex calls than controls (p<0.05). There were no changes in call latency or inter-call intervals. Spectrographic analysis revealed increased peak amplitude for complex, downward, short, two-syllable, and upward calls, as well as reduced mean duration for short and two-syllable calls in seizure mice. This investigation provides the first known spectrographic characterization of USVs following early-life seizures. These findings also enhance evidence for USVs as an indicator of select communicative impairment.

Characterization of the behavioral phenotype and neuroinflammatory profile of the Fmr1 knockout mouse

1986 The effects of dietary supplementation with n-3 fatty acids on the behavioral and neuroinflammatory phenotype of the Fmr1 knockout mouse S.O. Nolan, S.L. Hodges, G.D. Smith, B. Escobar, T. Jefferson, A. Holley, J.N. Lugo Baylor University, One Bear Place, Department of Psychology and Neuroscience, Waco, Texas 76798, USA FragileX Syndrome (FXS) is a neurodevelopmental disorder caused by a genetic trinucleotide (CGG) overexpansionmutation in the FMR1 gene coding for fragile X mental retardation protein (FMRP). This disorder is characterized by marked intellectual disability, as well as other autistic-like behavioral phenotypes. Supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFAs) has been proposed as an alternative treatment for a variety of neurodevelopmental disorders, including Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Previous results have examined the efficacy of this treatment paradigm in the FXS mouse model, though it is not known how the efficacy varies between background strains. In the present study, male FVB/129 Fmr1 knockout and Fmr1 wildtype littermates were assigned to one of three diet conditions following weaning on PD21: standard lab chow, EPA/DHA enriched chow, and a diet controlling for the increase in fat associated with the former. Upon reaching postnatal day 90, animals were tested in a several behavioral assays, which included elevated plus maze, social partition, nose poke assay, delay fear conditioning and prepulse inhibition. Results revealed that supplementation with omega-3 fatty acids attenuated alterations in prepulse inhibition behavior and hyperactivity. Results also revealed that the increased dietary fatty acid composition significantly impacted sociability and repetitive behavior. These behavioral changes were associated with reduction in hippocampal expression of IL-6 resulting from dietary supplementation omega-3 fatty acids. http://dx.doi.org/10.1016/j.bbi.2017.07.114