Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior

The Wnt/β-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/β-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior. TCF7L2 was the dominant Wnt effector that was expressed in both mouse and human astrocytes, with a peak during astrocyte maturation. The conditional knockout of Tcf7l2 in postnatal astrocytes led to an enlargement of astrocytes with defective tiling and gap junction coupling. These mice also exhibited an increase in the number of cortical excitatory and inhibitory synapses and a marked increase in social interaction by adulthood. These data reveal an astrocytic role for developmental Wnt/β-catenin signaling in restricting excitatory synapse numbers and regulating adult social behavior

Somatostatin-expressing interneurons modulate neocortical network through GABAb receptors in a synapse-specific manner

Abstract The firing activity of somatostatin-expressing inhibitory neurons (SST-INs) can suppress network activity via both GABAa and GABAb receptors (Rs). Although SST-INs do not receive GABAaR input from other SST-INs, it is possible that SST-IN-released GABA could suppress the activity of SST-INs themselves via GABAbRs, providing a negative feedback loop. Here we characterized the influence of GABAbR modulation on SST-IN activity in layer 2/3 of the somatosensory cortex in mice. We compared this to the effects of GABAbR activation on parvalbumin-expressing interneurons (PV-INs). Using in vitro whole-cell patch clamp recordings, pharmacological and optogenetic manipulations, we found that the firing activity of SST-INs suppresses excitatory drive to themselves via presynaptic GABAbRs. Postsynaptic GABAbRs did not influence SST-IN spontaneous activity or intrinsic excitability. Although GABAbRs at pre- and postsynaptic inputs to PV-INs are modestly activated during cortical network activity in vitro, the spontaneous firing of SST-INs was not the source of GABA driving this GABAbR activation. Thus, SST-IN firing regulates excitatory synaptic strength through presynaptic GABAbRs at connections between pyramidal neurons (Pyr-Pyr) and synapses between pyramidal neurons and SST-INs (Pyr-SST), but not Pyr-PV and PV-Pyr synapses. Our study indicates that two main types of neocortical inhibitory interneurons are differentially modulated by SST-IN-mediated GABA release

Presentation_1_GABAAR-mediated tonic inhibition differentially modulates intrinsic excitability of VIP- and SST- expressing interneurons in layers 2/3 of the somatosensory cortex.PPTX

Extrasynaptic GABAA receptors (GABAARs) mediating tonic inhibition are thought to play an important role in the regulation of neuronal excitability. However, little is known about a cell type-specific tonic inhibition in molecularly distinctive types of GABAergic interneurons in the mammalian neocortex. Here, we used whole-cell patch-clamp techniques in brain slices prepared from transgenic mice expressing red fluorescent protein (TdTomato) in vasoactive intestinal polypeptide- or somatostatin- positive interneurons (VIP-INs and SST-INs, respectively) to investigate tonic and phasic GABAAR-mediated inhibition as well as effects of GABAA inhibition on intrinsic excitability of these interneurons in layers 2/3 (L2/3) of the somatosensory (barrel) cortex. We found that tonic inhibition was stronger in VIP-INs compared to SST-INs. Contrary to the literature data, tonic inhibition in SST-INs was comparable to pyramidal (Pyr) neurons. Next, tonic inhibition in both interneuron types was dependent on the activity of delta subunit-containing GABAARs. Finally, the GABAAR activity decreased intrinsic excitability of VIP-INs but not SST-INs. Altogether, our data indicate that GABAAR-mediated inhibition modulates neocortical interneurons in a type-specific manner. In contrast to L2/3 VIP-INs, intrinsic excitability of L2/3 SST-INs is immune to the GABAAR-mediated inhibition.</p

Biomimetic alginate/perfluorocarbon microcapsules - tthe effect on in vitro metabolic activity and long-term cell culture

Cell encapsulation seems to be a promising tool in tissue engineering. However, it has been shown to have several limitations in terms of long-term cell cultures due to an insufficient oxygen supply. In this study we propose the use of novel microcapsules designed for long-term cell culture consisting of an alginate shell and perfluorocarbon (PFC) core, which works as a synthetic oxygen carrier and reservoir. The influence of PFC presence in the culture as well as the size of structures on cell metabolism was evaluated during 21-day cultures in normoxia and hypoxia. We showed significant improvement in cell metabolism in groups where cells were encapsulated in hydrogel structures with a PFC core. The cells maintained a typical metabolism (oxidative phosphorylation) through all 21 days of the culture, overcoming the oxygen supply shortage even in large structures (diameter ¡ 1 mm). Applying PFC in alginate matrices can improve cell metabolism and adaptation in long-term cell cultures

Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior.

The Wnt/β-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/β-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior. TCF7L2 was the dominant Wnt effector that was expressed in both mouse and human astrocytes, with a peak during astrocyte maturation. The conditional knockout of Tcf7l2 in postnatal astrocytes led to an enlargement of astrocytes with defective tiling and gap junction coupling. These mice also exhibited an increase in the number of cortical excitatory and inhibitory synapses and a marked increase in social interaction by adulthood. These data reveal an astrocytic role for developmental Wnt/β-catenin signaling in restricting excitatory synapse numbers and regulating adult social behavior