Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

Mutations in the synaptic scaffolding protein Shank3 are a major cause of autism, and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in mice, here we show that loss of Shank3 (Shank3B-/-) results in disrupted local and long-range prefrontal functional connectivity, as well as fronto-striatal decoupling. We document that prefrontal hypo-connectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.

Subglottal pressure, tracheal airflow, and intrinsic laryngeal muscle activity during rat ultrasound vocalization

Vocal production requires complex planning and coordination of respiratory, laryngeal, and vocal tract movements, which are incompletely understood in most mammals. Rats produce a variety of whistles in the ultrasonic range that are of communicative relevance and of importance as a model system, but the sources of acoustic variability were mostly unknown. The goal was to identify sources of fundamental frequency variability. Subglottal pressure, tracheal airflow, and electromyographic (EMG) data from two intrinsic laryngeal muscles were measured during 22-kHz and 50-kHz call production in awake, spontaneously behaving adult male rats. During ultrasound vocalization, subglottal pressure ranged between 0.8 and 1.9 kPa. Pressure differences between call types were not significant. The relation between fundamental frequency and subglottal pressure within call types was inconsistent. Experimental manipulations of subglottal pressure had only small effects on fundamental frequency. Tracheal airflow patterns were also inconsistently associated with frequency. Pressure and flow seem to play a small role in regulation of fundamental frequency. Muscle activity, however, is precisely regulated and very sensitive to alterations, presumably because of effects on resonance properties in the vocal tract. EMG activity of cricothyroid and thyroarytenoid muscle was tonic in calls with slow or no fundamental frequency modulations, like 22-kHz and flat 50-kHz calls. Both muscles showed brief high-amplitude, alternating bursts at rates up to 150 Hz during production of frequency-modulated 50-kHz calls. A differentiated and fine regulation of intrinsic laryngeal muscles is critical for normal ultrasound vocalization. Many features of the laryngeal muscle activation pattern during ultrasound vocalization in rats are shared with other mammals.

Tactile-Induced Ultrasonic Vocalization in the Rat: A Novel Assay to Assess Anti-Migraine Therapies in vivo

A pharmacological model of migraine is described using ultrasound vocalization (USV) of rats following central inflammation-induced sensitization to tactile stimulation. Central inflammation induced by intracerebroventricular injection of lipopolysaccharide (LPS) increased USV induced by an air current focused on the head and this was abolished by morphine and ketorolac, suggesting a nocice-ptive component. USV in naive rats were unaffected. Diazepam reduced USV in both inflamed and naive rats. The triptans, zolmitriptan and sumatriptan, both reduced USV in inflamed but not in naive rats, as did dihydroergotamine, and the calcitonin gene-related peptide (CGRP) antagonists αCGRP(8-37) and BIBN4096BS. The neurokinin-1 antagonist L-733-060 had no effect in either inflamed or naive rats when given after induction of inflammation, but when given with the LPS it prevented the augmentation of USV. This profile of activity of agents proven to be effective in the clinic suggests this model can be used to predict novel therapeutic agents for migraine.