Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms1,2. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD3,4. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component5–8. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5−/− mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.

Neurogenesis, the division, migration, and differentiation of new neurons, occurs throughout life. Brain derived neurotrophic factor (BDNF) has been identified as a potential signaling molecule regulating neurogenesis in the subventricular zone (SVZ), but its functional consequences in vivo have not been well defined. We report marked and unexpected deficits in survival but not proliferation of newly born cells of adult knock-in mice containing a variant form of BDNF [a valine (Val) to methionine (Met) substitution at position 66 in the prodomain of BDNF (Val66Met)], a genetic mutation shown to lead to a selective impairment in activity-dependent BDNF secretion. Utilizing knock-out mouse lines, we identified BDNF and tyrosine receptor kinase B (TrkB) as the critical molecules for the observed impairments in neurogenesis, with p75 knock-out mice showing no effect on cell proliferation or survival. We then localized the activated form of TrkB to a discrete population of cells, type A migrating neuroblasts, and demonstrate a decrease in TrkB phosphorylation in the SVZ of Val66Met mutant mice. With these findings, we identify TrkB signaling, potentially through activity dependent release of BDNF, as a critical step in the survival of migrating neuroblasts. Utilizing a behavioral task shown to be sensitive to disruptions in olfactory bulb neurogenesis, we identified specific impairments in spontaneous olfactory discrimination, but not general olfactory sensitivity or habituation to olfactory stimuli in BDNF mutant mice. Through these observations, we have identified novel links between genetic variant BDNF and adult neurogenesis in vivo, which may contribute to significant impairments in olfactory function.

SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56β, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.

Slitrks are a family of structurally-related transmembrane proteins belonging to the leucine-rich repeat (LRR) superfamily. Six family members exist (Slitrk1-Slitrk6), and all are highly expressed in the central nervous system (CNS). Slitrks have been implicated in mediating basic neuronal processes ranging from neurite outgrowth and dendritic elaboration to neuronal survival. Recent studies in humans and genetic mouse models have led to the identification of Slitrks as candidate genes that may be involved in the development of neuropsychiatric conditions such as obsessive compulsive spectrum disorders and schizophrenia. While these system level approaches have suggested that Slitrks play prominent roles in CNS development, key questions remain regarding the molecular mechanisms through which Slitrks mediate neuronal signaling and connectivity. SLITRK FAMILYThe Slitrk gene family is composed of six members (Slitrk1 -Slitrk6), which are highly expressed in the central nervous system (CNS) [1,2]. This family was identified in a screen for genes that were differentially expressed in mice with neural tube defects [1]. Slitrk5 had been previously discovered as a gene expressed in early hematopoietic progenitors but not in mature hematopoietic cells [3]. All Slitrks form single pass (type I) transmembrane proteins with an intracellular domain that varies in length [1]. At the extracellular domain, Slitrks contain two leucine-rich repeat (LRR) domains, which are each composed of 13 to 17 LRRs, flanked by cysteine rich domains (Glossary) [1]. Sequence analysis has revealed that the © 2011 Elsevier Ltd. All rights reserved. +Corresponding Authors: ccp2001@med.cornell.edu and fslee@med.cornell.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest statementThe authors declare no competing financial interests. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript extracellular LRR domains of Slitrks resembled Slit proteins, and a conserved region in their intracellular carboxyl terminus (C-terminus) has a high degree of consensus with the last 16 amino acids of the neurotrophin receptor, tropomyosin-related kinase (Trk) [1]. Based on their similarity with Slits and Trks, these proteins were named Slitrks [1].Slitrks are classified as members of the LRR superfamily, due to the presence of the LRR domains. The LRR superfamily is a class of molecules containing structural motifs of 20-29 amino acids with a defining sequence LxxLxLxxN/GxL (x being any amino acid) [4,5]. LRR domains are composed of tandem repeats of this L...