SummaryTourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding Lhistidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.Tourette's Syndrome is Characterized by Childhood Onset, Waxing and waning symptomatology, and typically, improvement in adulthood. The molecular underpinnings of the disorder remain uncertain, although multiple lines of evidence suggest involvement of dopaminergic neurotransmission and abnormalities involving cortical-striatal-thalamiccortical circuitry. 1 Current treatment focuses on tic reduction and management of prevalent coexisting conditions such as obsessive-compulsive disorder and attention deficithyperactivity disorder. However, therapeutic options have limited efficacy and may carry clinically significant side effects. Consequently, the development of new treatments based on an improved understanding of disease pathophysiology is a high priority. 2 The large genetic contribution to Tourette's syndrome is well established. 3 4,5 However, mutations are found in only a small proportion of affected persons, and the protein's normal function and the manner in which it may contribute to Tourette's syndrome are not yet well understood.In light of the probable genetic heterogeneity underlying Tourette's syndrome, we sought families in which the syndrome is transmitted in a mendelian fashion, which is rare. As has been shown for other complex disorders, gene discovery in such families may help to uncover molecular mechanisms of disease. 6 MethodsMethods are described briefly here; for complete details, see the Supplementary Appendix, available with the full text of this article at NEJM.org. All studies were approved by the Yale Institutional Review Board, and all participants provided written informed consent.A nonconsanguineous two-generation pedigree was referred to our laboratory (Fig. 1). The father and all eight offspring met the criteria for Tourette's syndrome in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (Table S1 in the Supplementary Appendix). Two children and the father also have obsessive-compulsive disorder. The mother, her parents, and her extended family are reportedly free from Tourette's syndrome, chronic tics, and obsessive-compulsive disorder.DNA samples from all family members in the two-generation pedigree were genotyped by means of Affymetrix GeneChip Human Mapping 100K Arrays and short-tandem-repeat markers that had been identified within the lod -2 linkage interval (the equivalent of a conf...

Successful addiction treatment depends on maintaining long-term abstinence, making relapse prevention an essential therapeutic goal. However, exposure to environmental cues associated with drug use often thwarts abstinence efforts by triggering drug using memories that drive craving and relapse. We sought to develop a dual approach for weakening cocaine memories through phosphoproteomic identification of targets regulated in opposite directions by memory extinction compared with reconsolidation in male Sprague-Dawley rats that had been trained to self-administer cocaine paired with an audiovisual cue. We discovered a novel, inversely regulated, memorydependent phosphorylation event on calcium-calmodulin-dependent kinase II ␣ (CaMKII␣) at serine (S)331. Correspondingly, extinction-associated S331 phosphorylation inhibited CaMKII␣ activity. Intra-basolateral amygdala inhibition of CaMKII promoted memory extinction and disrupted reconsolidation, leading to a reduction in subsequent cue-induced reinstatement. CaMKII inhibition had no effect if the memory was neither retrieved nor extinguished. Therefore, inhibition of CaMKII represents a novel mechanism for memory-based addiction treatment that leverages both extinction enhancement and reconsolidation disruption to reduce relapse-like behavior.

Several Rho GDP/GTP exchange factors include a Sec14 domain and spectrin repeats. The Sec14 domain of Kalirin 7 is a determinant of spine length. Together the noncatalytic Sec14 domain and spectrin repeats of Kalirin 7 support spine formation, localize to the postsynaptic density, and attract presynaptic endings.