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Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disease that causes progressive cognitive decline and neuropsychiatric symptoms (NPS) with apathy being highly common. The neurobiological mechanisms of apathy in AD are unclear. This study characterized apathy‐like behaviors in 5xFAD mice and their relationship to amyloid‐beta (Aβ) pathology in the hippocampus and prefrontal cortex (PFC). Method: We examined apathy‐like behavior in male and female 5xFAD mice and wild‐type controls at 6, 12, and 16 months of age (n=9‐14 per group). Behavioral paradigms included nest building, marble burying, and food burrowing, and we calculated apathy composite scores for each mouse from the results of these three tests. Then, we measured soluble Aβ42 in the hippocampus and PFC of the male and female 5xFAD mice with the highest and lowest apathy composites within each age group by ELISA assay. Finally, we characterized Aβ plaque density and size in the hippocampal CA1 subregion and the PFC using thioflavin‐S staining and ImageJ. Three‐way, independent sample ANOVAs were conducted to determine the effects of age, gender, and genotype or apathy status on behavioral or biochemical outcomes, respectively. Result: Apathy‐like behaviors occurred in 5xFAD mice at all ages (p<.0001 at 6, 12, and 16 months), and these behaviors became more prominent with age. Females displayed more apathetic‐like behaviors than males (p<.01). Soluble Aβ42 was substantially greater for 16‐month than 6‐month 5xFAD mice in the hippocampus (p<.0001) and PFC (p<.001) and for 12‐month than 6‐month 5xFAD mice in the hippocampus (p<.01). Higher apathy composites were associated with greater soluble Aβ42 in the PFC and more plaques in the CA1 subregion than lower apathy composites (p<.05 for both). In the PFC, female 5xFAD mice had more plaques than males (p<.01). Plaque density in the CA1 subregion and plaque size in the PFC were greater in 12‐month compared to 6‐month 5xFAD mice (p<.05 for both). Conclusion: This study demonstrates that 5xFAD mice display apathy‐like behaviors starting at 6 months that become significantly worse with age and potentially differ between sexes. Additionally, our study suggests correlations between apathy and soluble and insoluble Aβ pathology that differs by brain region. [ABSTRACT FROM AUTHOR]

Objectives: Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may clarify the underlying neurobiology of bvFTD-related NPS and guide development of therapies., Methodology: Participants (N=354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium. Dementia stage was defined as early (CDR ® plus NACC FTLD ≤ 1) or advanced (CDR ® plus NACC FTLD ≥ 1). Baseline and annual follow-up visit data were analyzed to compare NPS across stages of bvFTD. Psychiatric states were captured using the Neuropsychiatric Inventory-Questionnaire and Clinician Judgement of Symptoms. Polychoric cluster analysis was used to describe NPS clusters., Results: NPS were highly prevalent (≥ 90%) in early and late bvFTD. Four NPS clusters were identified based on magnitude of factor loadings: affective, disinhibited, compulsive, and psychosis. Neuropsychiatric symptoms fluctuated across visits. In the affective cluster, depression and anxiety showed the least visit-to-visit stability. In the disinhibited cluster, elation showed the least stability. Symptoms in the psychosis and compulsive clusters (hallucinations, delusions, obsessions/compulsions, and hyperorality) were largely stable, persisting from visit-to-visit in more than 50% of cases., Conclusion: NPS in bvFTD are frequent and cluster into four discrete groups in bvFTD. These clusters may result from specific neural network disruptions that could serve as targets for future interventions. The fluctuating nature of NPS in bvFTD suggests that they are not reliable markers of disease progression or stage.

PUMILIO 2 (PUM2) is a member of Pumilio and FBF (PUF) family, an RNA binding protein family with phylogenetically conserved roles in germ cell development. The Drosophila Pumilio homolog is also required for dendrite morphogenesis and synaptic function via translational control of synaptic proteins, such as glutamate receptors, and recent mammalian studies demonstrated a similar role in neuronal culture with associated motor and memory abnormalities in vivo . Importantly, transgenic mice with PUM2 knockout show prominent epileptiform activity, and patients with intractable temporal lobe epilepsy and mice with pilocarpine-induced seizures have decreased neuronal PUM2, possibly leading to further seizure susceptibility. However, how PUM2 influences synaptic function in vivo and, subsequently, seizures is not known. We found that PUM2 is highly expressed in the brain, especially in the temporal lobe, and knockout of Pum2 ( Pum2 -/- ) resulted in significantly increased pyramidal cell dendrite spine and synapse density. In addition, multiple proteins associated with excitatory synaptic function, including glutamate receptor 2 (GLUR2), are up-regulated in Pum2 -/- mice. The expression of GLUR2 protein but not mRNA is increased in the Pum2 -/- mutant hippocampus, Glur2 transcripts are increased in mutant polysome fractions, and overexpression of PUM2 led to repression of reporter expression containing the 3'Untranslated Region (3'UTR) of Glur2 , suggesting translation of GLUR2 was increased in the absence of Pum2 . Overall, these studies provide a molecular mechanism for the increased temporal lobe excitability observed with PUM2 loss and suggest PUM2 might contribute to intractable temporal lobe epilepsy., Competing Interests: CONFLICTS OF INTEREST None declared.