Role for the M₁ Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice

The M₁ muscarinic acetylcholine receptor (mAChR) subtype has been implicated in the underlying mechanisms of learning and memory and represents an important potential pharmacotherapeutic target for the cognitive impairments observed in neuropsychiatric disorders such as schizophrenia. Patients with schizophrenia show impairments in top-down processing involving conflict between sensory-driven and goal-oriented processes that can be modeled in preclinical studies using touchscreen-based cognition tasks. The present studies used a touchscreen visual pairwise discrimination task in which mice discriminated between a less salient and a more salient stimulus to assess the influence of the M₁ mAChR on top-down processing. M₁ mAChR knockout (M₁ KO) mice showed a slower rate of learning, evidenced by slower increases in accuracy over 12 consecutive days, and required more days to acquire (achieve 80% accuracy) this discrimination task compared to wild-type mice. In addition, the M₁ positive allosteric modulator BQCA enhanced the rate of learning this discrimination in wild-type, but not in M₁ KO, mice when BQCA was administered daily prior to testing over 12 consecutive days. Importantly, in discriminations between stimuli of equal salience, M₁ KO mice did not show impaired acquisition and BQCA did not affect the rate of learning or acquisition in wild-type mice. These studies are the first to demonstrate performance deficits in M₁ KO mice using touchscreen cognitive assessments and enhanced rate of learning and acquisition in wild-type mice through M₁ mAChR potentiation when the touchscreen discrimination task involves top-down processing. Taken together, these findings provide further support for M₁ potentiation as a potential treatment for the cognitive symptoms associated with schizophrenia

Rare and low-frequency coding variants alter human adult heigh

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways