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pubmed: 0006-3223

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Affected Anatomical Rich Club and Structural-Functional Coupling in Young Offspring of Schizophrenia and Bipolar Disorder Patients.
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Affected Anatomical Rich Club and Structural-Functional Coupling in Young Offspring of Schizophrenia and Bipolar Disorder Patients.

Biol Psychiatry. 2017 Jun 21;:

Authors: Collin G, Scholtens LH, Kahn RS, Hillegers MHJ, van den Heuvel MP

BACKGROUND: Emerging evidence suggests disruptions in the wiring organization of the brain's network in schizophrenia (SZ) and bipolar disorder (BD). As the importance of genetic predisposition has been firmly established in these illnesses, children (offspring) of patients constitute an at-risk population. This study examines connectome organization in children at familial high risk for psychosis.
METHODS: Diffusion-weighted magnetic resonance imaging scans were collected from 127 nonpsychotic offspring 8 to 18 years of age (average age = 13.5 years) of a parent diagnosed with SZ (SZ offspring; n = 28) or BD (BD offspring; N = 60) and community control subjects (n = 39). Resting-state functional magnetic resonance imaging scans were available for 82 subjects. Anatomical and functional brain networks were reconstructed and examined using graph theoretical analysis.
RESULTS: SZ offspring were found to show connectivity deficits of the brain's central rich club (RC) system relative to both control subjects and BD offspring. The disruption in anatomical RC connectivity in SZ offspring was associated with increased modularity of the functional connectome. In addition, increased coupling between structural and functional connectivity of long-distance connections was observed in both SZ offspring and BD offspring.
CONCLUSIONS: This study shows lower levels of anatomical RC connectivity in nonpsychotic young offspring of SZ patients. This finding suggests that the brain's anatomical RC system is affected in at-risk youths, reflecting a connectome signature of familial risk for psychotic illness. Moreover, finding no RC deficits in offspring of BD patients suggest a differential effect of genetic predisposition for SZ versus BD on the developmental formation of the connectome.

PMID: 28734460 [PubMed - as supplied by publisher]

The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression.
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The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression.

Biol Psychiatry. 2017 Jun 08;:

Authors: Maia TV, Conceição VA

Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively.

PMID: 28734459 [PubMed - as supplied by publisher]

Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement.
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Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement.

Biol Psychiatry. 2017 Jun 16;:

Authors: Soto D, Olivella M, Grau C, Armstrong J, Alcon C, Gasull X, Gómez de Salazar M, Gratacòs-Batlle E, Ramos-Vicente D, Fernández-Dueñas V, Ciruela F, Bayés À, Sindreu C, López-Sala A, García-Cazorla À, Altafaj X

BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p.P553T) coding for the GluN2B subunit of NMDAR.
METHODS: We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice.
RESULTS: Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p.P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation.
CONCLUSIONS: Our data suggest that hypofunctional NMDARs containing GluN2B(p.P553T) can contribute to Rett-like encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement.

PMID: 28734458 [PubMed - as supplied by publisher]