Developmental loss of MeCP2 from VIP interneurons impairs cortical function and behavior.
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ABSTRACT:
SUBMITTER: Mossner JM
PROVIDER: S-EPMC7213975 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:GABAergic interneurons play important roles in cortical circuit development. However, there are multiple populations of interneurons and their respective developmental contributions remain poorly explored. Neuregulin 1 (NRG1) and its interneuron-specific receptor ERBB4 are critical genes for interneuron maturation. Using a conditional ErbB4 deletion, we tested the role of vasoactive intestinal peptide (VIP)-expressing interneurons in the postnatal maturation of cortical circuits in vivo. ErbB4 removal from VIP interneurons during development leads to changes in their activity, along with severe dysregulation of cortical temporal organization and state dependence. These alterations emerge during adolescence, and mature animals in which VIP interneurons lack ErbB4 exhibit reduced cortical responses to sensory stimuli and impaired sensory learning. Our data support a key role for VIP interneurons in cortical circuit development and suggest a possible contribution to pathophysiology in neurodevelopmental disorders. These findings provide a new perspective on the role of GABAergic interneuron diversity in cortical development. VIDEO ABSTRACT.
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Project description:Neuronal tuning, defined by the degree of selectivity to a specific stimulus, is a hallmark of cortical computation. Understanding the role of GABAergic interneurons in shaping cortical tuning is now possible with the ability to manipulate interneuron classes selectively. Here, we show that interneurons expressing vasoactive intestinal polypeptide (VIP+) regulate the spatial frequency (SF) tuning of pyramidal neurons in mouse visual cortex. Using two-photon calcium imaging and optogenetic manipulations of VIP+ cell activity, we found that activating VIP+ cells elicited a stronger network response to stimuli of higher SFs, whereas suppressing VIP+ cells resulted in a network response shift toward lower SFs. These results establish that cortical inhibition modulates the spatial resolution of visual processing and add further evidence demonstrating that feature selectivity depends, not only on the feedforward excitatory projections into the cortex, but also on dynamic intracortical modulations by specific forms of inhibition.Significance statementWe demonstrate that interneurons expressing vasoactive intestinal polypeptide (VIP+) play a causal role in regulating the spatial frequency (SF) tuning of neurons in mouse visual cortex. We show that optogenetic activation of VIP+ cells results in a shift in network preference toward higher SFs, whereas suppressing them shifts the network toward lower SFs. Several studies have shown that VIP+ cells are sensitive to neuromodulation and increase their firing during locomotion, whisking, and pupil dilation and are involved in spatially specific top-down modulation, reminiscent of the effects of top-down attention, and also that attention enhances spatial resolution. Our findings provide a bridge between these studies by establishing the inhibitory circuitry that regulates these fundamental modulations of SF in the cortex.
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Project description:Attention deficit is one of the most prominent and disabling symptoms in Fragile X Syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in both humans and mice with FXS, but not their typically developing controls. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the post-stimulus period during early distractor trials in WT mice, consistent with their known role as 'error' signals. Strikingly, however, VIP cells from Fmr1-/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells, could be a potential therapeutic target for attentional difficulties in FXS.
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Project description:GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as a powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.
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Project description:Diverse subsets of cortical interneurons have vital roles in higher-order brain functions. To investigate how this diversity is generated, here we used single-cell RNA sequencing to profile the transcriptomes of mouse cells collected along a developmental time course. Heterogeneity within mitotic progenitors in the ganglionic eminences is driven by a highly conserved maturation trajectory, alongside eminence-specific transcription factor expression that seeds the emergence of later diversity. Upon becoming postmitotic, progenitors diverge and differentiate into transcriptionally distinct states, including an interneuron precursor state. By integrating datasets across developmental time points, we identified shared sources of transcriptomic heterogeneity between adult interneurons and their precursors, and uncovered the embryonic emergence of cardinal interneuron subtypes. Our analysis revealed that the transcription factor Mef2c, which is linked to various neuropsychiatric and neurodevelopmental disorders, delineates early precursors of parvalbumin-expressing neurons, and is essential for their development. These findings shed new light on the molecular diversification of early inhibitory precursors, and identify gene modules that may influence the specification of human interneuron subtypes.
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Project description:Rett Syndrome (RTT) is a neurodevelopmental disorder caused by loss of function of the transcriptional regulator Methyl-CpG-Binding Protein 2 (MeCP2). In addition to the characteristic loss of hand function and spoken language after the first year of life, people with RTT also have a variety of physiological and autonomic abnormalities including disrupted breathing rhythms characterized by bouts of hyperventilation and an increased frequency of apnea. These breathing abnormalities, that likely involve alterations in both the circuitry underlying respiratory pace making and those underlying breathing response to environmental stimuli, may underlie the sudden unexpected death seen in a significant fraction of people with RTT. In fact, mice lacking MeCP2 function exhibit abnormal breathing rate response to acute hypoxia and maintain a persistently elevated breathing rate rather than showing typical hypoxic ventilatory decline that can be observed among their wild-type littermates. Using genetic and pharmacological tools to better understand the course of this abnormal hypoxic breathing rate response and the neurons driving it, we learned that the abnormal hypoxic breathing response is acquired as the animals mature, and that MeCP2 function is required within excitatory, inhibitory, and modulatory populations for a normal hypoxic breathing rate response. Furthermore, mice lacking MeCP2 exhibit decreased hypoxia-induced neuronal activity within the nucleus tractus solitarius of the dorsal medulla. Overall, these data provide insight into the neurons driving the circuit dysfunction that leads to breathing abnormalities upon loss of MeCP2. The discovery that combined dysfunction across multiple neuronal populations contributes to breathing dysfunction may provide insight into sudden unexpected death in RTT.
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Project description:Neocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. Here, we show that ChAT-VIP neurons directly excite neighbouring neurons in several layers through fast synaptic transmission of acetylcholine (ACh) in rodent medial prefrontal cortex (mPFC). Both interneurons in layers (L)1-3 as well as pyramidal neurons in L2/3 and L6 receive direct inputs from ChAT-VIP neurons mediated by fast cholinergic transmission. A fraction (10-20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons. Finally, we show that activity of these neurons is relevant for behaviour and they control attention behaviour distinctly from basal forebrain ACh inputs. Thus, ChAT-VIP neurons are a local source of cortical ACh that directly excite neurons throughout cortical layers and contribute to attention.
| S-EPMC6872593 | biostudies-literature
Project description:Inhibitory interneurons expressing vasoactive intestinal polypeptide (VIP) are known to disinhibit cortical neurons. However, it is unclear how disinhibition, occurring at the single-cell level, interacts with network-level patterns of activity to shape complex behaviors. To address this, we examined the role of prefrontal VIP interneurons in a widely studied mouse behavior: deciding whether to explore or avoid the open arms of an elevated plus maze. VIP interneuron activity increases in the open arms and disinhibits prefrontal responses to hippocampal inputs, which are known to transmit signals related to open arm avoidance. Indeed, inhibiting VIP interneurons disrupts network-level representations of the open arms and decreases open arm avoidance specifically when hippocampal-prefrontal theta synchrony is strong. Thus, VIP interneurons effectively gate the ability of hippocampal input to generate prefrontal representations, which drive avoidance behavior. This shows how VIP interneurons enable cortical circuits to integrate specific inputs into network-level representations that guide complex behaviors. VIDEO ABSTRACT.
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Project description:We applied massively parallel single-cell RNA-seq to profile a developmental time course of interneuron development, measuring the transcriptomes of over 60,000 progenitors during their maturation in the ganglionic eminences and embryonic migration into the cortex.
2018-03-05 | GSE104158 | GEO
Project description:Vasocative-intestinal-peptide (VIP+) and somatostatin (SST+) interneurons are involved in modulating barrel cortex activity and perception during active whisking. Here we identify a developmental transition point of structural and functional rearrangements onto these interneurons around the start of active sensation at P14. Using in vivo two-photon Ca2+ imaging, we find that before P14, both interneuron types respond stronger to a multi-whisker stimulus, whereas after P14 their responses diverge, with VIP+ cells losing their multi-whisker preference and SST+ neurons enhancing theirs. Additionally, we find that Ca2+ signaling dynamics increase in precision as the cells and network mature. Rabies virus tracings followed by tissue clearing, as well as photostimulation-coupled electrophysiology reveal that SST+ cells receive higher cross-barrel inputs compared to VIP+ neurons at both time points. In addition, whereas prior to P14 both cell types receive direct input from the sensory thalamus, after P14 VIP+ cells show reduced inputs and SST+ cells largely shift to motor-related thalamic nuclei.
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