Attention-Deficit/Hyperactivity Disorder: Focus upon Aberrant N-Methyl-d-Aspartate Receptors Systems

Abstract

Attention-deficit/hyperactivity disorder (ADHD) pathophysiology persists in an obscure manner with complex interactions between symptoms, staging, interventions, genes, and environments. Only on the basis of increasing incidence of the disorder, the need for understanding is greater than ever. The notion of an imbalance between central inhibitory/excitatory neurotransmitters is considered to exert an essential role. In this chapter, we first review how the default mode network functions and dysfunction in individuals diagnosed with ADHD. We also present and briefly review some of the animal models used to examine the neurobiological aspects of ADHD. There is much evidence indicating that compounds/interventions that antagonize/block glutamic acid receptors and/or block the glutamate signal during the "brain growth spurt" or in the adult animal may induce functional and biomarker deficits. Additionally, we present evidence suggesting that animals treated with glutamate blockers at the period of the "brain growth spurt" fail to perform the exploratory activity, observed invariably with control mice, that is associated with introduction to a novel environment (the test cages). Later, when the control animals show less locomotor and rearing activity, i.e., interest in the test cages, the MK-801, ketamine and ethanol treated mice showed successively greater levels of locomotion and rearing (interest), i.e., they fail to "habituate" effectively, implying a cognitive dysfunction. These disturbances of glutamate signaling during a critical period of brain development may contribute to the ADHD pathophysiology. As a final addition, we have briefly identified new research venues in the interaction between ADHD, molecular studies, and personality research.

Altered Development of Synapse Structure and Function in Striatum Caused by Parkinson's Disease-Linked LRRK2-G2019S Mutation

“…By P60, sEPSC frequencies were similar across all genotypes (Table 1), similar to what has been observed in adult mice overexpressing LRRK2-G2019S (Beccano-Kelly et al, 2015). Our data suggest that developmental abnormalities in synaptic neurotransmission at P21 in GSKI mice may trigger compensatory mechanisms as circuits mature.…”

“…Action potential-dependent vesicle fusion (sEPSCs) and spontaneous vesicle fusion (mEPSCs) can involve different vesicle pools (Sara et al, 2005;Kavalali, 2015) and produce distinct postsynaptic consequences (Sutton et al, 2006(Sutton et al, , 2007, raising the possibility that G2019S could be differentially affecting one or the other modes of vesicle release. To examine specifically effects of the G2019S mutation on spontaneous presynaptic vesicle release, we recorded mEPSCs at P21 after the addition of TTX (3 M) into the bath to eliminate all action potential-mediated presynaptic activity.…”

“…Parkinson's disease (PD) is a progressive neurological disorder characterized by impairments in motor and nonmotor functions of the dorsal striatum (Shiba et al, 2000;Goedert, 2001;Aarsland et al, 2009;Gerfen and Surmeier, 2011;Erro et al, 2012). The majority of inherited forms of PD are caused by mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), most of which reside in the GTPase or kinase domains of LRRK2 (Paisán-Ruiz et al, 2004;Zimprich et al, 2004;Di Fonzo et al, 2005;Khan et al, 2005;Ozelius et al, 2006;Cookson, 2010).…”

“…fMRI data show altered functional connectivity between cortex and striatum in asymptomatic human LRRK2-G2019S carriers , and although there is disagreement over mechanism, loss-of-function studies of LRRK2 or its orthologs in Caenorhabditis elegans, Drosophila, and mouse support that wild-type (WT) LRRK2 can regulate developing synapse function (Sakaguchi-Nakashima et al, 2007;Shin et al, 2008;Lee et al, 2010b;Piccoli et al, 2011;Beccano-Kelly et al, 2014;Parisiadou et al, 2014). In brain, LRRK2 is most highly expressed in striatal spiny projection neurons (SPNs).…”

“…To test this, we used LRRK2 mutant knockin (KI) mice to compare gain-and loss-of-LRRK2 kinase function. This strategy circumvents confounding experimental factors, such as protein overexpression and mixed expression of WT and mutant LRRK2 proteins that have complicated interpretation of LRRK2 experiments performed in transgenic mouse models (Aarsland et al, 2009;Dächsel et al, 2010;Li et al, 2010;Skibinski et al, 2014). Our findings reveal that LRRK2-G2019S exerts a robustly abnormal effect on corticostriatal synapses at postnatal day 21 (P21).…”