Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors

Abstract

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74-/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PLPNs–dSTRFSIs) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PLPNs–BLAPNs) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL–dSTR or PL–BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL–dSTR and PL–BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice

“…The OFT has been widely used to analyze locomotor activity, anxiety-like, and repetitive behaviors in rodent ASD [14,29,30]. See supplementary methods for further details.…”

“…Animals were randomly assigned to the experimental groups. The sample size (n) for different experiments is indicated in each figure legend and was determined according to the preliminary results and the standards generally used in the field [29,35,45]. Results were analyzed by two population Student's t-test, or two-way ANOVA followed by post hoc Bonferroni's test, or two-way repeated measures (RM) ANOVA followed by post hoc Sidak's test, as indicated in the figure legends.…”

“…The medial prefrontal cortex (mPFC) includes the prelimbic (PrL), infralimbic, and anterior cingulate cortices in rodents. PrL pyramidal neurons, which project to various brain areas, play important roles in emotion, cognition, and social behavior [27][28][29]; Dysfunction of the PrL neural circuit has been shown to be associated with autistic-like behaviors [29,30]. Therefore, we aimed to understand the role of RFWD2 in neuronal development and function in the mPFC region.…”

Scn2a insufficiency alters spontaneous neuronal Ca2+ activity in somatosensory cortex during wakefulness

“…While the somatosensory cortex was implicated in ASD, in particular the altered tactile response observed in patients, 28 , 29 other brain regions such as the prefrontal cortex also plays a critical role in social and cognitive function. 59 , 60 Our ability to examine multiple brain regions simultaneously is limited by the field of view of the current in vivo Ca 2+ imaging platform. However, future studies could build upon these existing observations and perform in vivo imaging in other brain regions in the Scn2a ASO mice.…”

Age-Related Changes of Dopamine D1 and D2 Receptors Expression in Parvalbumin-Positive Cells of the Orbitofrontal and Prelimbic Cortices of Mice

“…The PrL is more associated with executive functions (Baker & Ragozzino, 2014; Broschard, Kim, Love, Wasserman, & Freeman, 2021) and emotional regulation (Mears, Boutros, & Cromwell, 2009), whereas the OFC plays a particular role in the evaluation of rewards and punishments, guiding appropriate behavioral responses (Frontera et al, 2023; Lichtenberg et al, 2021). Dysfunction in the PrL has been implicated in disorders such as anxiety (Luo et al, 2023). In contrast, damage to the OFC can lead to changes in social behavior and decision- making (Bolla et al, 2003; du Plessis et al, 2018).…”