Inhibitory interneurons in the dorsolateral geniculate nucleus (dLGN) are situated at the first central synapse of the image-forming visual pathway, but little is known about their function. Given their anatomy, they are expected to be multiplexors, integrating many different retinal channels along their dendrites. Here, using targeted single-cell-initiated rabies tracing, we found that mouse dLGN interneurons exhibit a degree of retinal input specialization similar to thalamocortical neurons. Some are anatomically highly specialized, for example, toward motion-selective information. Two-photon calcium imaging performed in vivo revealed that interneurons are also functionally specialized. In mice lacking retinal horizontal direction selectivity, horizontal direction selectivity is reduced in interneurons, suggesting a causal link between input and functional specialization. Functional specialization is not only present at interneuron somata but also extends into their dendrites. Altogether, inhibitory interneurons globally display distinct visual features which reflect their retinal input specialization and are ideally suited to perform feature-selective inhibition.

A recent study by Hadler and colleagues uncovered a novel form of plasticity of gamma oscillations in an ex vivo hippocampal slice preparation which they term \'gamma potentiation\'. We discuss the potential cellular mechanisms of this form of plasticity and its functional and translational implications.

The plasticity of inhibitory interneurons (INs) plays an important role in the organization and maintenance of cortical microcircuits. Given the many different IN types, there is an even greater diversity in synapse-type-specific plasticity learning rules at excitatory to excitatory (E→I), I→E, and I→I synapses. I→I synapses play a key disinhibitory role in cortical circuits. Because they typically target other INs, vasoactive intestinal peptide (VIP) INs are often featured in I→I→E disinhibition, which upregulates activity in nearby excitatory neurons. VIP IN dysregulation may thus lead to neuropathologies such as epilepsy. In spite of the important activity regulatory role of VIP INs, their long-term plasticity has not been described. Therefore, we characterized the phenomenology of spike-timing-dependent plasticity (STDP) at inputs and outputs of genetically defined VIP INs. Using a combination of whole-cell recording, 2-photon microscopy, and optogenetics, we explored I→I STDP at layer 2/3 (L2/3) VIP IN outputs onto L5 Martinotti cells (MCs) and basket cells (BCs). We found that VIP IN→MC synapses underwent causal long-term depression (LTD) that was presynaptically expressed. VIP IN→BC connections, however, did not undergo any detectable plasticity. Conversely, using extracellular stimulation, we explored E→I STDP at inputs to VIP INs which revealed long-term potentiation (LTP) for both causal and acausal timings. Taken together, our results demonstrate that VIP INs possess synapse-type-specific learning rules at their inputs and outputs. This suggests the possibility of harnessing VIP IN long-term plasticity to control activity-related neuropathologies such as epilepsy.

GABAergic neurons represent 10-15% of the neuronal population of the cortex but exert a powerful control over information flow in cortical circuits. The largest GABAergic class in the neocortex is represented by the parvalbumin-expressing fast-spiking neurons, which provide powerful somatic inhibition to their postsynaptic targets. Recently, the density of parvalbumin interneurons has been shown to be lower in associative areas of the mouse cortex as compared with sensory and motor areas. Modelling work based on these quantifications linked the low-density of parvalbumin interneurons with specific computations of associative cortices. However, it is still unknown whether the total GABAergic population of association cortices is smaller or whether another GABAergic type can compensate for the low density of parvalbumin interneurons. In the present study, we investigated these hypotheses using a combination of neuroanatomy, mouse genetics and neurophysiology. We found that the GABAergic population of association areas is comparable with that of primary sensory areas, and it is enriched of fast-spiking neurons that do not express parvalbumin and were not accounted for by previous quantifications. We developed an intersectional viral strategy to demonstrate that the population of fast-spiking neurons is comparable across cortical regions. Our results provide quantifications of the density of fast-spiking GABAergic neurons and offers new biological constrains to refine current models of cortical computations.

Inhibitory interneurons in the spinal dorsal horn (DH) play a major role in regulating innocuous and noxious information. Reduction in inhibitory synaptic transmission is thought to contribute to the development of touch-evoked pain (allodynia), a common symptom of neuropathic pain. However, it is not fully understood how inhibitory neurons in the DH regulate sensory responses in surrounding neurons and modulate sensory transmission. In this study, we established a novel experimental method to analyze temporal activity of DH neurons during the optogenetically induced disinhibition state by combining extracellular recording and optogenetics. We investigated how specific and temporally restricted dysfunction of DH inhibitory neurons affected spinal neuronal activities evoked by cutaneous mechanical stimulation. In behavioral experiments, the specific and temporally restricted spinal optogenetic suppression of DH inhibitory neurons induced mechanical hypersensitivity. Furthermore, this manipulation enhanced the mechanical responses of wide dynamic range (WDR) neurons, which are important for pain transmission, in response to brush and von Frey stimulation but not in response to nociceptive pinch stimulation. In addition, we examined whether a neuropathic pain medication, mirogabalin, suppressed these optogenetically induced abnormal pain responses. We found that mirogabalin treatment attenuated the abnormal firing responses of WDR neurons and mechanical hypersensitivity. These results suggest that temporally restricted and specific reduction of spinal inhibitory neuronal activity facilitates the mechanical responses of WDR neurons, resulting in neuropathic-like mechanical allodynia which can be suppressed by mirogabalin. Our optogenetic methods could be useful for developing novel therapeutics for neuropathic pain.

Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.

The functional properties of the human brain arise, in part, from the vast assortment of cell types that pattern the cortex. The cortical sheet can be broadly divided into distinct networks, which are further embedded into processing streams, or gradients, that extend from unimodal systems through higher-order association territories. Here, using transcriptional data from the Allen Human Brain Atlas, we demonstrate that imputed cell type distributions are spatially coupled to the functional organization of cortex, as estimated through fMRI. Cortical cellular profiles follow the macro-scale organization of the functional gradients as well as the associated large-scale networks. Distinct cellular fingerprints were evident across networks, and a classifier trained on post-mortem cell-type distributions was able to predict the functional network allegiance of cortical tissue samples. These data indicate that the in vivo organization of the cortical sheet is reflected in the spatial variability of its cellular composition.

Inhibitory interneurons expressing parvalbumin (PV) play critical roles throughout the brain. Their rapid spiking enables them to control circuit dynamics on a millisecond time scale, and the timing of their activation by different excitatory pathways is critical to these functions. We used a genetically encoded hybrid voltage sensor to image PV interneuron voltage changes with sub-millisecond precision in primary somatosensory barrel cortex (BC) of adult mice. Electrical stimulation evoked depolarizations with a latency that increased with distance from the stimulating electrode, allowing us to determine conduction velocity. Spread of responses between cortical layers yielded an interlaminar conduction velocity and spread within layers yielded intralaminar conduction velocities in different layers. Velocities ranged from 74 to 473 μm/ms depending on trajectory; interlaminar conduction was 71% faster than intralaminar conduction. Thus, computations within columns are more rapid than between columns. The BC integrates thalamic and intracortical input for functions such as texture discrimination and sensory tuning. Timing differences between intra- and interlaminar PV interneuron activation could impact these functions. Imaging of voltage in PV interneurons reveals differences in signaling dynamics within cortical circuitry. This approach offers a unique opportunity to investigate conduction in populations of axons based on their targeting specificity.

UNASSIGNED: According to our previous study, the loss of inhibitory interneuron function contributes to central sensitization in chronic migraine (CM). Synaptic plasticity is a vital basis for the occurrence of central sensitization. However, whether the decline in interneuron-mediated inhibition promotes central sensitization by regulating synaptic plasticity in CM remains unclear. Therefore, this study aims to explore the role of interneuron-mediated inhibition in the development of synaptic plasticity in CM.
UNASSIGNED: A CM model was established in rats by repeated dural infusion of inflammatory soup (IS) for 7 days, and the function of inhibitory interneurons was then evaluated. After intraventricular injection of baclofen [a gamma-aminobutyric acid type B receptor (GABABR) agonist] or H89 [a protein kinase A (PKA) inhibitor), behavioral tests were performed. The changes in synaptic plasticity were investigated by determining the levels of the synapse-associated proteins postsynaptic density protein 95 (PSD95), synaptophysin (Syp) and synaptophysin-1(Syt-1)]; evaluating the synaptic ultrastructure by transmission electron microscopy (TEM); and determining the density of synaptic spines via Golgi-Cox staining. Central sensitization was evaluated by measuring calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), c-Fos and substance P (SP) levels. Finally, the PKA/Fyn kinase (Fyn)/tyrosine-phosphorylated NR2B (pNR2B) pathway and downstream calcium-calmodulin-dependent kinase II (CaMKII)/c-AMP-responsive element binding protein (pCREB) signaling were assessed.
UNASSIGNED: We observed dysfunction of inhibitory interneurons, and found that activation of GABABR ameliorated CM-induced hyperalgesia, repressed the CM-evoked elevation of synapse-associated protein levels and enhancement of synaptic transmission, alleviated the CM-triggered increases in the levels of central sensitization-related proteins, and inhibited CaMKII/pCREB signaling via the PKA/Fyn/pNR2B pathway. The inhibition of PKA suppressed the CM-induced activation of Fyn/pNR2B signaling.
UNASSIGNED: These data reveal that the dysfunction of inhibitory interneurons contributes to central sensitization by regulating synaptic plasticity through the GABABR/PKA/Fyn/pNR2B pathway in the periaqueductal gray (PAG) of CM rats. Blockade of GABABR-pNR2B signaling might have a positive influence on the effects of CM therapy by modulating synaptic plasticity in central sensitization.

Synapses in the brain exhibit cell-type-specific differences in basal synaptic transmission and plasticity. Here, we evaluated cell-type-specific specializations in the composition of glutamatergic synapses, identifying Btbd11 as an inhibitory interneuron-specific, synapse-enriched protein. Btbd11 is highly conserved across species and binds to core postsynaptic proteins, including Psd-95. Intriguingly, we show that Btbd11 can undergo liquid-liquid phase separation when expressed with Psd-95, supporting the idea that the glutamatergic postsynaptic density in synapses in inhibitory interneurons exists in a phase-separated state. Knockout of Btbd11 decreased glutamatergic signaling onto parvalbumin-positive interneurons. Further, both in vitro and in vivo, Btbd11 knockout disrupts network activity. At the behavioral level, Btbd11 knockout from interneurons alters exploratory behavior, measures of anxiety, and sensitizes mice to pharmacologically induced hyperactivity following NMDA receptor antagonist challenge. Our findings identify a cell-type-specific mechanism that supports glutamatergic synapse function in inhibitory interneurons-with implications for circuit function and animal behavior.