, 2008; Wang et al., 2010), a recent genome-wide screen showed that the GRM gene family encoding mGluRs, most frequently GRM5, and genes interacting with it are enriched for CNVs in ADHD ( Elia et al., 2012; Lesch et al., 2012b). ADHD is characterized by developmentally inappropriate inattention, hyperactivity, increased impulsivity and emotional dysregulation with a specific constellation of deficits in motivation, working memory and cognitive control of executive functions, thus displaying syndromal overlap with ASD. Other CNV findings concerned GRM1 duplications, GRM7 deletions, and GRM8 deletions. Overall the findings indicate that up to 10% of individuals

with ADHD may be enriched for mGluR network variants. Several of these genes play a central role in the process of neurogenesis, synaptic transmission and network connectivity that has been argued to be defective SCH727965 clinical trial in ADHD. Specifically, mGluRs modulate mRNA generation, alternative splicing and translation, processes known to influence circuitry-specific formation, activity and

plasticity of synapses ( Bockaert et al., 2010; Knafo and Esteban, 2012). Disruption of frontostriatal circuitries which are involved in motor control and action learning, is thought to represent a specific characteristic of ADHD pathophysiology click here (Cubillo et al., 2012; de Zeeuw et al., 2012). Enhanced short-range connectivity within motivation-reward networks and their decreased connectivity with structures Carnitine dehydrogenase comprising the default-mode and dorsal attention networks have been reported, indicating impaired crosstalk among cognitive control and reward pathways that may reflect attentional and motivational deficits in ADHD (Tomasi and Volkow, 2012; Volkow et al., 2012). Since it is abundantly expressed in dendritic spines of structural units of the frontostriatal circuit including

nucleus accumbens, dorsal striatum and PFC, mGluR5 not only interacts with signaling of dopamine and 5-HT receptors but also with NMDA receptors, resulting in reciprocal and agonist-independent inhibition of the two receptors (Perroy et al., 2008). While mGluR5 is confined to the periphery of the synapse, NMDA receptors are located vis-à-vis of the glutamate release site in the PSD comprising the multiprotein HOMER-SHANK-GKAP-PSD-95 scaffolding complex physically and functionally linking the two receptors (Fagni et al., 2008). Moreover, the nucleus accumbens and dorsal striatum receive extensive serotonergic input mediated by a multitude of 5-HT receptors including subtypes 5-HT1-4 (Figure 2). 5-HT activates 5-HT1B receptors resulting in a cAMP-dependent LTD-associated decrease of glutamate release and striatal output (Mathur et al., 2011; Navailles and De Deurwaerdere, 2011). This 5-HT-induced LTD is independent of dopamine, suggesting that serotonergic and dopaminergic signaling pathways both interact in corticostriatal circuit plasticity.