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In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired hippocampus-dependent memory, but the underlying mechanism remains elusive. Given that hippocampal cholinergic systems modulate memory and rapid development of hippocampal cholinergic systems occurs during nicotine exposure, here we investigated its impacts on cholinergic function. Both nicotinic and muscarinic activation produce transient or long-lasting depression of excitatory synaptic transmission in the hippocampal CA1 region. We found that postnatal nicotine exposure impairs both the induction and nicotinic modulation of NMDAR-dependent long-term depression (LTD). Activation of muscarinic receptors decreases excitatory synaptic transmission and CA1 network activity in both wild-type and α2 knockout mice. These muscarinic effects are still observed in nicotine-exposed mice. M1 muscarinic receptor activity is required for mGluR-dependent LTD. Early postnatal nicotine exposure has no effect on mGluR-dependent LTD induction, suggesting that it has no effect on the function of m1 muscarinic receptors involved in this form of LTD. Our results demonstrate that early postnatal nicotine exposure has more pronounced effects on nicotinic function than muscarinic function in the hippocampal CA1 region. Thus, impaired hippocampus-dependent memory may arise from the developmental disruption of nicotinic cholinergic systems in the hippocampal CA1 region., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Our understanding of the determinants of quality of life (QOL) in people living with Parkinson's disease and related disorders (PDRD) has grown remarkably in the past decade. However, several areas remain understudied including determinants of general vs. health-related QOL, determinants in high-need patients, drivers of perceptions of caregivers vs. patients, and exploration of potential determinants outside of the traditional medical model., Methods: This was a cross-sectional study of 210 PDRD patients and 175 caregivers who completed a battery of measures regarding general QOL (QOL-Alzheimer's disease; QOL-AD), health-related QOL (Parkinson's disease Questionnaire; PDQ-39), cognitive function, mood, grief, spiritual wellbeing, symptom burden, disease severity, disease stage, overall function, socioeconomic status, and healthcare utilization. Elastic net regularization modeling of variables significantly associated with our outcomes of interest were performed to determine predictors of general QOL, compare predictors of general vs. health-related QOL, and compare predictors of patient and caregiver perspectives on patient general QOL., Results: General QOL was associated with spiritual wellbeing, depression, cognitive function, presence of a caregiver, and recent emergency department visits. In contrast, health-related QOL was associated with grief, symptom burden, income, disease stage, and utilization of counseling services. Caregiver ratings of patient general QOL were associated with patient symptom burden, patient grief, patient global function, caregiver burden, and caregiver spiritual wellbeing., Conclusions: There are notable differences in the predictors of general QOL, health-related QOL and caregiver perspectives on patient general QOL. These differences have important implications for clinical research and models of clinical care., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Fragile X syndrome (FXS) is an inherited intellectual impairment that results from the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein that regulates mRNA translation at synapses. The absence of FMRP leads to neuronal and circuit-level hyperexcitability that is thought to arise from the aberrant expression and activity of voltage-gated ion channels, although the identification and characterization of these ion channels have been limited. Here, we show that FMRP binds the mRNA of the R-type voltage-gated calcium channel Cav2.3 in mouse brain synaptoneurosomes and represses Cav2.3 translation under basal conditions. Consequently, in hippocampal neurons from male and female FMRP KO mice, we find enhanced Cav2.3 protein expression by western blotting and abnormally large R currents in whole-cell voltage-clamp recordings. In agreement with previous studies showing that FMRP couples Group I metabotropic glutamate receptor (GpI mGluR) signaling to protein translation, we find that GpI mGluR stimulation results in increased Cav2.3 translation and R current in hippocampal neurons which is disrupted in FMRP KO mice. Thus, FMRP serves as a key translational regulator of Cav2.3 expression under basal conditions and in response to GpI mGluR stimulation. Loss of regulated Cav2.3 expression could underlie the neuronal hyperactivity and aberrant calcium spiking in FMRP KO mice and contribute to FXS, potentially serving as a novel target for future therapeutic strategies. SIGNIFICANCE STATEMENT Patients with fragile X syndrome (FXS) exhibit signs of neuronal and circuit hyperexcitability, including anxiety and hyperactive behavior, attention deficit disorder, and seizures. FXS is caused by the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein, and the neuronal hyperexcitability observed in the absence of FMRP likely results from its ability to regulate the expression and activity of voltage-gated ion channels. Here we find that FMRP serves as a key translational regulator of the voltage-gated calcium channel Cav2.3 under basal conditions and following activity. Cav2.3 impacts cellular excitability and calcium signaling, and the alterations in channel translation and expression observed in the absence of FMRP could contribute to the neuronal hyperactivity that underlies FXS., (Copyright © 2019 the authors.)