Phenotypic complexities of rare heterozygous neurexin-1 deletions.

Given the large number of genes significantly associated with risk for neuropsychiatric disorders, a critical unanswered question is the extent to which diverse mutations --sometimes impacting the same gene-- will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions in , a pre-synaptic cell adhesion protein that serves as a critical synaptic organizer in the brain.

γ-Protocadherins control synapse formation and peripheral branching of touch sensory neurons.

Light touch sensation begins with activation of low-threshold mechanoreceptor (LTMR) endings in the skin and propagation of their signals to the spinal cord and brainstem. We found that the clustered protocadherin gamma (Pcdhg) gene locus, which encodes 22 cell-surface homophilic binding proteins, is required in somatosensory neurons for normal behavioral reactivity to a range of tactile stimuli. Developmentally, distinct Pcdhg isoforms mediate LTMR synapse formation through neuron-neuron interactions and peripheral axonal branching through neuron-glia interactions.

ASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs.

Background: Somatic cell reprogramming is routinely used to generate donor-specific human induced pluripotent stem cells (hiPSCs) to facilitate studies of disease in a human context. The directed differentiation of hiPSCs can generate large quantities of patient-derived cells; however, such methodologies frequently yield heterogeneous populations of neurons and glia that require extended timelines to achieve electrophysiological maturity. More recently, transcription factor-based induction protocols have been show to rapidly generate defined neuronal populations from hiPSCs.

THC Treatment Alters Glutamate Receptor Gene Expression in Human Stem Cell-Derived Neurons.

Given the cognitive and behavioral effects following in utero Δ9-tetrahydrocannabinol (THC) exposure that have been reported in humans and rodents, it is critical to understand the precise consequences of THC on developing human neurons. Here, we utilize excitatory neurons derived from human-induced pluripotent stem cells (hiPSCs), and report that in vitro THC exposure reduced expression of glutamate receptor subunit genes (, , and ). By expanding these studies across hiPSC-derived neurons from individuals with a variety of genotypes, we believe that a hiPSC-based model will facilitate studies of the interaction of THC exposure and the genetic risk factors underlying neuropsychiatric disease vulnerability.

Using hiPSCs to model neuropsychiatric copy number variations (CNVs) has potential to reveal underlying disease mechanisms.

Schizophrenia is a neuropsychological disorder with a strong heritable component; genetic risk for schizophrenia is conferred by both common variants of relatively small effect and rare variants with high penetrance. Genetically engineered mouse models can recapitulate rare variants, displaying some behavioral defects associated with schizophrenia; however, these mouse models cannot recapitulate the full genetic architecture underlying the disorder. Patient-derived human induced pluripotent stem cells (hiPSCs) present an alternative approach for studying rare variants, in the context of all other risk alleles.