SummaryThe most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene [1]. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language [2]. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning [3, 4]. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits.

Multi-unit electrophysiological mapping was used to establish the area of the left- and right-hemisphere auditory cortex (AC) of the mouse and to characterize various fields within the AC. The AC of the left hemisphere covered a significantly larger (factor of 1.30) area compared to that of the right side. Based on best-frequency (BF) maps and other neuronal response characteristics to tone and noise bursts, five fields (primary auditory field, anterior auditory field, second auditory field, ultrasonic field, dorsoposterior field) and two small non-specified areas could be delimited on both hemispheres. The relative sizes of these fields and areas were similar on both sides. The primary and anterior auditory fields were tonotopically organized with counter running frequency gradients merging in the center of the AC. These fields covered BF ranges up to about 45 kHz. Higher BFs up to about 70 kHz were represented non-tonotopically in the separate ultrasonic field, part of which may be considered as belonging to the primary field. The dorsoposterior and second auditory fields were non-tonotopically organized and neurons had special response properties. These characteristics of the mouse AC were compared with auditory cortical maps of other mammals.

Components of the communication system between infant and adult rodents based on ultrasonic vocalizations (USVs) of infants are analyzed. USVs are most often emitted from a pup lost outside the nest in response to changes of: (i) body temperature, (ii) contact with adults/littermates, (iii) handling, and (iv) smell. These changes modulate the state of arousal and the emotional/motivational states and, as a result, USVs are produced. Acoustic properties of USVs seem to reflect the degrees of changes in arousal and emotion/motivation. Adult rodents are aroused by perceiving the USVs, locate the sender and show a phonotaxic approach to the sender. Acoustic properties of USVs in the frequency and time domains are described based on which adult rodents discriminate the USVs from other ultrasounds and take the USVs or adequate models of them as preferred goals of their phonotaxic approach. The preferred approach to adequate USVs is modulated by emotions/motivations, the sex of the receiver, hormonal states, experience with pups and neurotransmitter systems of the brain. The phonotaxis can be understood as the appetitive component of a pup-caring instinct. The consummatory act of the instinct is the retrieval of the lost pup. This retrieval is independent of USV presence, but it closes the communication loop activated by the emission of USVs. Communication with USVs can be used as a tool to investigate genetic and brain mechanisms of behavioral control.

Proteins of the ProSAP/Shank family act as major organizing scaffolding elements within the postsynaptic density of excitatory synapses. Deletions, mutations or the downregulation of these molecules has been linked to autism spectrum disorders, the related Phelan McDermid Syndrome or Alzheimer's disease. ProSAP/Shank proteins are targeted to synapses depending on binding to zinc, which is a prerequisite for the assembly of the ProSAP/Shank scaffold. To gain insight into whether the previously reported assembly of ProSAP/Shank through zinc ions provides a crossing point between genetic forms of autism spectrum disorder and zinc deficiency as an environmental risk factor for autism spectrum disorder, we examined the interplay between zinc and ProSAP/Shank in vitro and in vivo using neurobiological approaches. Our data show that low postsynaptic zinc availability affects the activity dependent increase in ProSAP1/Shank2 and ProSAP2/Shank3 levels at the synapse in vitro and that a loss of synaptic ProSAP1/Shank2 and ProSAP2/Shank3 occurs in a mouse model for acute and prenatal zinc deficiency. Zinc-deficient animals displayed abnormalities in behaviour such as over-responsivity and hyperactivity-like behaviour (acute zinc deficiency) and autism spectrum disorder-related behaviour such as impairments in vocalization and social behaviour (prenatal zinc deficiency). Most importantly, a low zinc status seems to be associated with an increased incidence rate of seizures, hypotonia, and attention and hyperactivity issues in patients with Phelan-McDermid syndrome, which is caused by haploinsufficiency of ProSAP2/Shank3. We suggest that the molecular underpinning of prenatal zinc deficiency as a risk factor for autism spectrum disorder may unfold through the deregulation of zinc-binding ProSAP/Shank family members.

In humans, sound perceived as speech is processed preferentially by the right ear and the left hemisphere of the brain. Among animals, such an advantage of one hemisphere (lateralization) in processing communication sound from other members of the species has so far been demonstrated only in macaque monkeys. I report here that in the house mouse, which has a very much less elaborate forebrain than man or macaque monkey, the ultrasonic calls that are emitted by young mice to evoke maternal caring behavior are preferentially recognized by the left hemisphere. In females with no experience of pups, which have been trained to respond to the same ultrasonic calls by conditioning, no advantage for one hemisphere is detected. The results suggest that lateralization of this function evolved early in mammals and emphasize that an innate predisposition for perceiving communication sounds is connected with a left-hemisphere advantage in processing them. This experimental system is a readily-available animal model for studying lateralized auditory brain functions.