GABAergic and glycinergic interneuron expression during spinal cord development: Dynamic interplay between inhibition and excitation in the control of ventral network outputs
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Interneuron
Abstract Interneurons are GABAergic neurons responsible for inhibitory activity in the adult hippocampus, thereby controlling the activity of principal excitatory cells through the activation of postsynaptic GABAA receptors. Subgroups of GABAergic neurons innervate specific parts of excitatory neurons. This specificity indicates that particular interneuron subgroups are able to recognize molecules segregated on the membrane of the pyramidal neuron. Once these specific connections are established, a quantitative regulation of their strength must be performed to achieve the proper balance of excitation and inhibition. We will review when and where interneurons are generated. We will then detail their migration toward and within the hippocampus, and the maturation of their morphological and neurochemical characteristics. We will finally review potential mechanisms underlying the development of GABAergic interneurons. © 2006 Wiley‐Liss, Inc.
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Inhibitory GABAergic interneurons have been extensively studied but their contribution to circuit dynamics remain poorly understood. Although it has been suggested that interneurons, especially those belonging to the same subclass, synchronize their activity and impart this synchrony onto their local network, recent theoretical and experimental work have challenged this view. To better understand the activity of interneurons during cortical activity, we combined molecular identification, two-photon imaging, and electrophysiological recordings in thalamocortical slices from mouse somatosensory cortex. Using calcium imaging to monitor cortical activity, we found low spiking correlations among parvalbumin or somatostatin interneurons during cortical UP states, indicating that interneurons do not synchronize their firing. Intracellular recordings confirmed that nearby interneurons do not display more synchronous spiking than excitatory cells. The lack of interneuron synchrony was also evident during slow oscillations, even among interneurons that were electrically coupled via gap junctions, suggesting that their coupling does not function to synchronize their activity. Using voltage-clamp recordings from nearby pyramidal cells, we found that inhibitory currents (IPSCs) are more correlated than excitatory ones, but that correlated IPSCs arise from the activation of common presynaptic inhibitory cells, rather than from synchronization of interneuron activity. Finally, we demonstrate that pharmacologically reducing inhibitory currents increases correlated excitatory activity. We conclude that inhibitory interneurons do not have synchronous activity during UP states, and that their function may be to decorrelate rather than to synchronize the firing of neurons within the local network.
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Throughout early phases of brain development, the two main neural signaling mechanisms-excitation and inhibition-are dynamically sculpted in the neocortex to establish primary functions. Despite its relatively late formation and persistent developmental changes, the GABAergic system promotes the ordered shaping of neuronal circuits at the structural and functional levels. Within this frame, interneurons participate first in spontaneous and later in sensory-evoked activity patterns that precede cortical functions of the mature brain. Upon their subcortical generation, interneurons in the embryonic brain must first orderly migrate to and settle in respective target layers before they can actively engage in cortical network activity. During this process, changes at the molecular and synaptic level of interneurons allow not only their coordinated formation but also the pruning of connections as well as excitatory and inhibitory synapses. At the postsynaptic site, the shift of GABAergic signaling from an excitatory towards an inhibitory response is required to enable synchronization within cortical networks. Concomitantly, the progressive specification of different interneuron subtypes endows the neocortex with distinct local cortical circuits and region-specific modulation of neuronal firing. Finally, the apoptotic process further refines neuronal populations by constantly maintaining a controlled ratio of inhibitory and excitatory neurons. Interestingly, many of these fundamental and complex processes are influenced-if not directly controlled-by electrical activity. Interneurons on the subcellular, cellular, and network level are affected by high frequency patterns, such as spindle burst and gamma oscillations in rodents and delta brushes in humans. Conversely, the maturation of interneuron structure and function on each of these scales feeds back and contributes to the generation of cortical activity patterns that are essential for the proper peri- and postnatal development. Overall, a more precise description of the conducting role of interneurons in terms of how they contribute to specific activity patterns-as well as how specific activity patterns impinge on their maturation as orchestra members-will lead to a better understanding of the physiological and pathophysiological development and function of the nervous system.
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In his theory of functional polarity, Ramon y Cajal first identified the soma and dendrites as the principal recipient compartments of a neuron and the axon as its main output structure. Despite notable exceptions in other parts of the nervous system (Schoppa and Urban, 2003; Wässle, 2004; Howard et al., 2005), this route of signal propagation has been shown to underlie the functional properties of most neocortical circuits studied so far. Recent evidence, however, suggests that neocortical excitatory cells may trigger the release of the inhibitory neurotransmitter GABA by directly depolarizing the axon terminals of inhibitory interneurons, thus bypassing their somatodendritic compartments (Ren et al., 2007). By using a combination of optical and electrophysiological approaches, we find that synaptically released glutamate fails to trigger GABA release through a direct action on GABAergic terminals under physiological conditions. Rather, our evidence suggests that glutamate triggers GABA release only after somatodendritic depolarization and action potential generation at GABAergic interneurons. These data indicate that neocortical inhibition is recruited by classical somatodendritic integration rather than direct activation of interneuron axon terminals.
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Abstract The classical view of striatal GABAergic interneuron function has been that they operate as largely independent, parallel, feedforward inhibitory elements providing inhibitory inputs to spiny projection neurons (SPNs). Much recent evidence has shown that the extrinsic innervation of striatal interneurons is not indiscriminate but rather very specific, and that striatal interneurons are themselves interconnected in a cell type‐specific manner. This suggests that the ultimate effect of extrinsic inputs on striatal neuronal activity depends critically on synaptic interactions within interneuronal circuitry. Here, we compared the cortical and thalamic input to two recently described subtypes of striatal GABAergic interneurons, tyrosine hydroxylase‐expressing interneurons (THINs), and spontaneously active bursty interneurons (SABIs) using transgenic TH‐Cre and Htr3a‐Cre mice of both sexes. Our results show that both THINs and SABIs receive strong excitatory input from the motor cortex and the thalamic parafascicular nucleus. Cortical optogenetic stimulation also evokes disynaptic inhibitory GABAergic responses in THINs but not in SABIs. In contrast, optogenetic stimulation of the parafascicular nucleus induces disynaptic inhibitory responses in both interneuron populations. However, the short‐term plasticity of these disynaptic inhibitory responses is different suggesting the involvement of different intrastriatal microcircuits. Altogether, our results point to highly specific interneuronal circuits that are selectively engaged by different excitatory inputs.
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Alteration in the excitatory/inhibitory neuronal balance is believed to be the underlying mechanism of epileptogenesis. Based on this theory, GABAergic interneurons are regarded as the primary inhibitory neurons, whose failure of action permits hyperactivity in the epileptic circuitry. As a consequence, optogenetic excitation of GABAergic interneurons is widely used for seizure suppression. However, recent evidence argues for the context-dependent, possibly "excitatory" roles that GABAergic cells play in epileptic circuitry. We reviewed current optogenetic approaches that target the "inhibitory" roles of GABAergic interneurons for seizure control. We also reviewed interesting evidence that supports the "excitatory" roles of GABAergic interneurons in epileptogenesis. GABAergic interneurons can provide excitatory effects to the epileptic circuits via several distinct neurological mechanisms. (1) GABAergic interneurons can excite postsynaptic neurons, due to the raised reversal potential of GABA receptors in the postsynaptic cells. (2) Continuous activity in GABAergic interneurons could lead to transient GABA depletion, which prevents their inhibitory effect on pyramidal cells. (3) GABAergic interneurons can synchronize network activity during seizure. (4) Some GABAergic interneurons inhibit other interneurons, causing disinhibition of pyramidal neurons and network hyperexcitability. The dynamic, context-dependent role that GABAergic interneurons play in seizure requires further investigation of their functions at single cell and circuitry level. New optogenetic protocols that target GABAergic inhibition should be explored for seizure suppression.
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The proper development and function of neuronal circuits rely on a tightly regulated balance between excitatory and inhibitory (E/I) synaptic transmission, and disrupting this balance can cause neurodevelopmental disorders, for example, schizophrenia. MicroRNA-dependent gene regulation in pyramidal neurons is important for excitatory synaptic function and cognition, but its role in inhibitory interneurons is poorly understood. Here, we identify miR138-5p as a regulator of short-term memory and inhibitory synaptic transmission in the mouse hippocampus. Sponge-mediated miR138-5p inactivation specifically in mouse parvalbumin (PV)-expressing interneurons impairs spatial recognition memory and enhances GABAergic synaptic input onto pyramidal neurons. Cellular and behavioral phenotypes associated with miR138-5p inactivation are paralleled by an upregulation of the schizophrenia (SCZ)-associated Erbb4 , which we validated as a direct miR138-5p target gene. Our findings suggest that miR138-5p is a critical regulator of PV interneuron function in mice, with implications for cognition and SCZ. More generally, they provide evidence that microRNAs orchestrate neural circuit development by fine-tuning both excitatory and inhibitory synaptic transmission.
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Local field potential
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