Dlx5/6 regulate perineuronal net-synapse coupling and stabilize adult cortical Parvalbumin neurons networks

Astrocytic NFIX regulates thalamocortical circuits through GABA and purinergic signaling.

Astrocytes support synaptic activity and associated circuit function, including those linked to sleep and memory, though how they coordinate these processes remains poorly defined. Here, we show that the transcription factor Nuclear Factor I-X (NFIX) is required to maintain astrocyte function in the thalamic reticular nucleus (TRN), as its deletion results in aberrant thalamocortical oscillations and impaired memory formation. We found that NFIX directly regulates the expression of monoamine oxidase B (MAOB) and the purinergic receptor, P2RX7. Mechanistically, knockdown of Maob or knockout of P2rx7 in TRN astrocytes results in decreased astrocytic release of the neurotransmitter GABA, reducing tonic inhibition of ventrobasal (VB) relay neurons and impairing memory formation. Altogether, our studies identify region-specific roles for astrocytic NFIX and its gene regulatory network in TRN astrocytes, while further revealing that astrocytes in the TRN couple regulation of thalamocortical circuit dynamics and memory formation through parallel GABA and purinergic signaling pathways.

Neuropil aggrecan, not perineuronal nets, closes the critical period for visual plasticity

Perineuronal nets (PNNs) are widely reported to close developmental critical periods and restrict experience-dependent plasticity. Here we tested this model by selectively eliminating gene expression for aggrecan (Acan), an essential component of PNNs. In visual cortex, PNNs predominantly ensheath parvalbumin-positive (PV+) interneurons. Deletion of Acan in inhibitory neurons eliminated PNNs but did not prevent closure of the critical period. By comparison, deletion of Acan in all neurons, or only in excitatory forebrain neurons, sustained critical-period plasticity in adult mice. Visual plasticity in adults was associated with reduced cortical excitatory synaptic inputs onto layer 2/3 PV+ interneurons and increased expression of some immediate early genes in visual cortex but normal response strength and tuning properties of layer 2/3 excitatory neurons. These findings rectify long-standing models that misattribute closure of the critical period to PNNs and identify that aggrecan expressed by excitatory neurons resident in the surrounding neuropil limits visual plasticity.

Sensory experience and mTORC1 interplay orchestrates the maturation of cortical interneuron connectivity and tactile sensitivity

Sensory abnormalities are core features of neurodevelopmental disorders, including autism. Although interneuron dysfunction is hypothesized to contribute to these deficits, the underlying mechanisms remain unclear. Here, we demonstrate that mTORC1 dysregulation in parvalbumin-expressing (PV) interneurons drives heightened tactile exploration and defensiveness. These behavioral changes coincide with whisker-evoked cortical responses characterized by increased power but degraded temporal precision. Excitatory inputs to PV cells, their intrinsic excitability and in vivo firing rate during tactile exploration are reduced, suggesting that mutant PV cells are hypoactive. Whisker trimming restricted to the third postnatal week prevented mTORC1 hyperactivation, PV cell input and output connectivity deficits as well as abnormal tactile cortical responses and behavior in adult mutant mice. Further, this manipulation rescued sociability deficits. Altogether, these data suggest that the interplay between mTORC1 signaling and sensory experience in PV cells regulates their connectivity, and contributes to the proper development of tactile and social behavior.

Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders

The hippocampus forms memories of our experiences in populations of coactive pyramidal neurons (PNs)1–3. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus–CA3/CA2 circuit of the hippocampus precisely control PN activity through mossy fibre-dependent feedforward inhibition4–11. PV INs coordinate experience-dependent changes in their intrinsic excitability, synaptic connectivity, physiology and plasticity properties9,12–15—referred to here as experience-dependent PV IN plasticity—to regulate PN activity. PV IN impairments in early life, when neural circuitry is highly sensitive to experience, are thought to result in network hyperexcitability, seizures and impaired cognition, which are hallmarks of neurodevelopmental disorders (NDDs)16–18. Here we designed an input-specific translatome screen to identify regulators of experience-dependent PV IN plasticity genes (XPGs) in the CA3/CA2 subregion of adult hippocampus. We demonstrate that a substantial proportion of upregulated candidate XPGs exhibit haploinsufficiency in autism spectrum disorder, epilepsies, bipolar disorder and schizophrenia, which suggests that there is impaired experience-dependent PV IN plasticity in NDDs. In proof-of-concept experiments, targeted upregulation of a candidate XPG, the homeobox gene Meis2 (ref. 19), in CA3/CA2 PV INs in an NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity. Moreover, ensemble and sharp-wave ripple properties and cognition were improved, and seizures were suppressed. Thus, experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.

Perineuronal nets preferentially surround parvalbumin interneurons in the prelimbic cortex: A rat and mouse comparison.

Recent work has shown the importance of perineuronal nets (PNNs) in modulating neuronal function and plasticity. Functional studies increasingly manipulate PNNs to probe their role in learning and memory, yet interpreting these manipulations requires knowing which cell types PNNs surround, information that remains incomplete for several brain regions. This study focuses on the prelimbic cortex to determine the percentage of specific interneurons and pyramidal cells that are surrounded by PNNs in male rats and mice. We used immunohistochemistry to assess prelimbic cortex cells containing parvalbumin (PV), glutamate decarboxylase (GAD65/67), and/or calcium kinase II (CamKII), and Wisteria floribunda agglutinin to identify PNNs. Cells with PV, GAD65/67 and/or CamKII were counted and the percentage with PNNs was calculated. Among the cell types examined, PV-expressing interneurons showed the highest frequency of PNN association in the prelimbic cortex of both rats and mice, followed by GAD65/67-expressing interneurons. No CamKII-positive cells had PNNs in rats or mice. PV-only and GAD-only cells were much more likely to have PNNs in mice than in rats. In both species, a small percentage of PNNs surround cells that had no detectable immunolabeling. These findings indicate that PV interneurons are most likely to have PNNs in layers 5/6 of the prelimbic cortex, but species differences suggest caution in designing and interpreting experiments that manipulate PNNs, particularly when generalizing between rat and mouse models.

Visual deprivation in adulthood engages presynaptic plasticity of thalamocortical synapses