Region-specific Foxp2 deletions in cortex, striatum or cerebellum cannot explain vocalization deficits observed in spontaneous global knockouts

Abstract

FOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension. Disruptions of the murine orthologue Foxp2 in mouse pups have been shown to interfere with production of ultrasonic vocalizations (USVs). However, it remains unclear which structures are responsible for these deficits. Here, we show that conditional knockout mice with selective Foxp2 deletions targeting the cerebral cortex, striatum or cerebellum, three key sites of motor control with robust neural gene expression, do not recapture the profile of pup USV deficits observed in mice with global disruptions of this gene. Moreover, we observed that global Foxp2 knockout pups show substantive reductions in USV production as well as an overproduction of short broadband noise “clicks”, which was not present in the brain region-specific knockouts. These data indicate that deficits of Foxp2 expression in the cortex, striatum or cerebellum cannot solely explain the disrupted vocalization behaviours in global Foxp2 knockouts. Our findings raise the possibility that the impact of Foxp2 disruption on USV is mediated at least in part by effects of this gene on the anatomical prerequisites for vocalizing.

Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation

“…In contrast, short calls were associated with larger volume in the corpus callosum, cingulate cortex, and subiculum, and smaller thalamic and cerebellar volume. Previous studies have found that neurotypical pup calls tend to be clustered in short sequences, thus, longer vocalizations may be indicative of some abnormal development or distress (52). Importantly, these patterns may be more expressed in both early and late MIA-exposed neonates.…”

Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation in mice

“…In contrast, short calls were associated with larger volume in the corpus callosum, cingulate cortex, and subiculum, and smaller thalamic and cerebellar volume. Previous studies have found that neurotypical pup calls tend to be clustered in short sequences, thus, longer vocalizations may be indicative of some abnormal development or distress ( Urbanus et al, 2020 ). Importantly, these patterns were similar between groups, with a slightly stronger expression in the POL L group and slightly weaker expression in the POL E group, an association requiring future investigation.…”

Molecular networks of the FOXP2 transcription factor in the brain

“…Foxp2 expression in the mouse cortex, striatum, and cerebellum modulates different aspects of motor function, as demonstrated by conditional homozygous knockouts targeting these structures (French et al , 2019 ). However, selective deletion of the gene in each of these brain regions does not significantly alter production of ultrasonic vocalizations (Urbanus et al , 2020 ). Interestingly, while selective deletion of Foxp2 in the mouse cortex does not appear to impact development of cortical structures during embryogenesis (Co et al , 2019 ; Kast et al , 2019 ), cortical‐specific knockouts are reported to nonetheless show altered social behaviors (Co et al , 2019 ; Medvedeva et al , 2019 ).…”