Attention Deficit-Hyperactivity Disorder (ADHD): From Abnormal Behavior to Impairment in Synaptic Plasticity.

Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high incidence in children and adolescents characterized by motor hyperactivity, impulsivity, and inattention. Magnetic resonance imaging (MRI) has revealed that neuroanatomical abnormalities such as the volume reduction in the neocortex and hippocampus are shared by several neuropsychiatric diseases such as schizophrenia, autism spectrum disorder and ADHD. Furthermore, the abnormal development and postnatal pruning of dendritic spines of neocortical neurons in schizophrenia, autism spectrum disorder and intellectual disability are well documented. Dendritic spines are dynamic structures exhibiting Hebbian and homeostatic plasticity that triggers intracellular cascades involving glutamate receptors, calcium influx and remodeling of the F-actin network. The long-term potentiation (LTP)-induced insertion of postsynaptic glutamate receptors is associated with the enlargement of spine heads and long-term depression (LTD) with spine shrinkage. Using a murine model of ADHD, a delay in dendritic spines' maturation in CA1 hippocampal neurons correlated with impaired working memory and hippocampal LTP has recently reported. The aim of this review is to summarize recent evidence that has emerged from studies focused on the neuroanatomical and genetic features found in ADHD patients as well as reports from animal models describing the molecular structure and remodeling of dendritic spines.

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol-requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an 5xFAD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the AD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

Methylphenidate Restores Behavioral and Neuroplasticity Impairments in the Prenatal Nicotine Exposure Mouse Model of ADHD: Evidence for Involvement of AMPA Receptor Subunit Composition and Synaptic Spine Morphology in the Hippocampus.

In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH.

Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis.

Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.

Atomoxetine Reestablishes Long Term Potentiation in a Mouse Model of Attention Deficit/Hyperactivity Disorder.

Attention deficit/hyperactivity disorder (ADHD) is the most prevalent psychiatric childhood disorder, characterized by hyperactivity, impulsivity and impaired attention, treated most frequently with methylphenidate (MPH). For children and adults with ADHD who do not respond satisfactorily or do not tolerate well stimulants such as MPH or D-Amphetamine, for them the alternative is to use Atomoxetine (ATX), a norepinephrine (NE) transporter inhibitor that increase extracellular NE. We examined the effects of ATX on behavior and hippocampal synaptic plasticity in the murine prenatal nicotine exposure (PNE) model of ADHD. ADHD symptoms were measured using behavioral tests, open field for hyperactivity and the Y-maze for spatial working memory. Further, ATX effects on long-term potentiation (LTP) in hippocampal slices at the CA3-CA1 synapse were assessed. PNE mice exhibited the behavioral deficits of ADHD, hyperactivity and spatial memory impairment. Intraperitoneal injection of ATX (2 mg/kg/day) normalized these behaviors significantly after 7 days. In PNE mice LTP was reduced (110.6 ±â€¯4.5% %; n = 7) compared to controls (148.9 ±â€¯5.2%; n = 7; p < 0.05). ATX administration (5 µM) reestablished the LTP in PNE mice to levels similar to the controls (157.7 ±â€¯6.3%; n = 7). Paired-pulse ratios (PPR) were not significantly different for any condition. These results indicate that administration of ATX in a PNE model of ADHD reestablishes TBS-dependent LTP in CA3-CA1 synapses. The results suggest postsynaptic changes in synaptic plasticity as part of the mechanisms that underlie improvement of ADHD symptoms induced by ATX.

Single and Repeated Administration of Methylphenidate Modulates Synaptic Plasticity in Opposite Directions via Insertion of AMPA Receptors in Rat Hippocampal Neurons.

Methylphenidate (MPH) is widely used in the treatment of Attention Deficit Hyperactivity Disorder. Several lines of evidence support that MPH can modulate learning and memory processes in different ways including improvement and impairment of test performances. A relevant factor in the efficacy of treatment is whether administration is performed once or several times. In this study we demonstrate opposite effects of MPH on performance of preadolescent rats in the Morris Water Maze test. Animals treated with a single dose (1 mg/kg) performed significantly better compared to controls, while in animals treated with repetitive administration at the same concentration performance was reduced. We found that hippocampal LTP in slices from rats treated with a single dose was increased, while LTP from rats treated with repetitive injections of MPH was lower than in controls. Using Western blot of CA1 areas from potentiated slices of rats treated with a single dose we found a significant increase of phosphorylation at Ser845 of GluA1 subunits, associated to an increased insertion of GluA1-containing AMPARs in the plasma membrane. These receptors were functional, because AMPA-dependent EPSCs recorded on CA1 were enhanced, associated to a significant increase in short-term plasticity. In contrast, CA1 samples from rats injected with MPH during six consecutive days, showed a significant decrease in the phosphorylation at Ser845 of GluA1 subunits associated to a lower insertion of GluA1-containing AMPARs. Accordingly, a reduction of the AMPA-mediated EPSCs and short-term plasticity was also observed. Taken together, our results demonstrate that single and repeated doses with MPH can induce opposite effects at behavioral, cellular, and molecular levels. The mechanisms demonstrated here in preadolescent rats are relevant to understand the effects of this psychostimulant in the treatment of ADHD.

A new semisynthetic derivative of sauroine induces LTP in hippocampal slices and improves learning performance in the Morris Water Maze.

Two semisynthetic acetyl derivatives of the alkaloid sauroine from Huperzia saururus, monoacetyl sauroine, and diacetyl sauroine (DAS) were obtained and their chemical structures were analyzed by NMR. While monoacetyl sauroine is the typical product of acetylation, DAS is an unexpected derivative related to the keto-enol formation of sauroine. Recordings of field excitatory post-synaptic potentials from the CA1 region of rat hippocampal slices showed that only DAS acutely applied induced chemical long-term potentiation (LTP) in a dose-dependent manner with an EC50 of 1.15 ± 0.09 µM. This effect was blocked by 10 µM D(-)-2-amino-5-phosphonopentanoic acid (AP5), suggesting dependence on the NMDA receptor. DAS significantly increased NMDA receptor-dependent excitatory post-synaptic currents without affecting α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor-dependent currents. Repetitive administration of DAS improved visuo-spatial learning in the Morris Water Maze. In slices from rats tested in the Morris Water Maze, LTP resulting from electrical synaptic stimulation was 2.5 times larger than in controls. Concentration of DAS measured in the brain after repetitive administration was 29.5 µM. We conclude that slices perfused with DAS display a robust NMDA receptor-dependent chemical LTP. During chronic treatment, DAS enhances learning abilities through a metaplastic mechanism as revealed by the augmentation of LTP in slices. DAS, therefore, may be a promising compound as a nootropic therapeutic drug. A semisynthetic derivative of sauroine, diacetyl sauroine (DAS), induces chemical long-term potentiation in rat hippocampal slices increasing the NMDA receptor-dependent current. 2 mg/kg prior to each session in a Morris Water Maze (MWM) improves behavior performance. In slices prepared from the tested rats the electrical stimulation-dependent long-term potentiation (LTP) was greatly enhanced. Therefore, DAS may have potency as a nootropic drug against the memory decline.