For instance, parvalbumin-containing basket cells express voltage-gated potassium channels of the Kv3 family, which contributes essentially to the "fast-spiking" behavior of these neurons, allowing them to respond to incoming synaptic input with minimal delay, and to sustain high-frequency spiking activity in response to strong input.
Differences in the expression of voltage-gated ion channels between interneuron types also underlies the differential dependence of the subthreshold voltage response on the frequency of stimulation "impedance profile". Some neuronal classes show distinct peaks " resonances " in their impedance profiles at characteristic frequencies, which may contribute to their differential involvement in the generation of network oscillations in various frequency bands.
Finally, both excitatory synapses onto interneurons and the inhibitory synapses formed by interneurons on local principal cells have physiological properties that depend on interneuronal class.
Synapses may differ in the amplitude and kinetics of the postsynaptic response. Many glutamatergic synapses onto interneurons activate Ca-permeable AMPA-type receptors lacking the GluR2 subunit, which is an important determinant of the rapid synaptic signaling that characterizes these connections. In the sections below, the two largest classes of cortical interneurons i. The precise site of termination as well as specific input characteristics allows to dissect this cell group into three major types.
Axo-axonic, or chandelier cells innervate exclusively the axon initial segments of principal cells, and occur both in the hippocampus and in the neocortex. Each axo-axonic cell forms radially running rows of boutons that climb along the axon initial segments of about pyramidal cells. Due to the strategic location of their axon terminals, axo-axonic cells have been claimed to simultaneously inhibit output from large principal cell populations.
However, recent evidence suggests that their postsynaptic GABAA -receptor-mediated effect may be depolarizing, and, as a consequence, they may be able to discharge the entire pyramidal cell population they innervate, with the aim of synchronizing their output, or to reset conductances in their dendritic trees. In the hippocampus, axo-axonic cell bodies are located within or near the pyramidal cell layer, and have radially running dendritic trees that span all layers, although a few exceptions may have dendrites confined to stratum oriens.
Axo-axonic cells can be recruited by both feed-forward and feed-back input. Their firing activity is suppressed during and after hippocampal sharp wave-associated ripple oscillations which are associated with synchronous discharges of CA3 pyramidal cells. However, axo-axonic cells often increase their firing just before ripple episodes. Their activity is phase-coupled to the peak of the theta waves recorded extracellularly in stratum pyramidale.
The remaining types of Perisomatic Inhibitory cells are basket cells that form multiple synaptic contacts on the somata and proximal dendrites of principal cells, each basket cell targeting about of them. The transverse extent of basket cell axonal arbours in the hippocampus was found to be about 1 mm. Basket cells are present in many different brain areas including the cerebral and the cerebellar cortices in the cerebellum, they inhibit Purkinje cells.
In the neocortex and the hippocampus, several subtypes of basket cell have been distinguished. The parvalbumin PV -containing basket cell bodies are located within or near stratum pyramidale, and have radially running dendrites that span all layers.
They are driven very efficiently by feed-forward excitatory input, as evidenced, for example, by the tight temporal coupling of the firing of PV-containing basket cells in CA1 to characteristic population activity patterns in CA3 in vivo, although many of them also receive input from local principal cells in a feed-back manner. The cholecystokinin CCK -containing basket cell bodies can be located in all layers, but typically in stratum radiatum, and have radially running dendritic trees spanning all layers.
CCK basket cells generally receive far less local glutamatergic inputs than PV cells, but are selectively innervated by serotonergic afferents from the median raphe via 5HT3 receptors. They also express nicotinic alpha7 and alpha4, as well as presynaptic cannabinoid CB1 , GABAB and estrogen1 receptors, and form synapses on pyramidal cell bodies and dendrites largely via GABAA receptors enriched in alpha2 subunits.
In contrast to PV basket cells, their predominant local drive is feed-back, and due to their large membrane time constants they are uniquely capable of summating feed-forward and feed-back drives over long time windows. During theta activity, both basket cell types fire at the peak of extracellularly recorded field potential waves out of phase with pyramidal cells, which fire at the trough , with PV cell firing shifted slightly towards the descending, and CCK cell firing towards the ascending phase.
While PV cells strongly increase their firing during sharp waves, CCK cell discharges remain unchanged. This is consistent with the fact that CCK cells can be activated only by a combination of feed-back and feed-forward drives, while ripples in CA1 are driven by CA3 in a feed-forward manner. Although both basket cell types are primarily responsible for rhythmic synchronization of the activity of large principal cell populations at theta and gamma frequencies, there is a considerable division of labour between them associated with their differential behaviour during sharp waves, and with different excitatory drives.
A synthesis of the above features led to the proposal Freund, that the electrically and synaptically coupled, and mostly locally driven, ensembles of PV-containing basket cells are indispensable components of the oscillating cortical hardware; they represent a precision clockwork without which no cortical operations are possible.
The activity of a similar syncytium of CCK-containing basket cells is superimposed on the PV basket cell-entrained network, conveying emotional and motivational effects carried by serotonergic and cholinergic pathways. In addition, actions of the CCK cell ensemble are highly modifiable by local neuromodulators and retrograde signal molecules, which may allow further fine tuning of principal cell cooperation.
Impairment of this tuning system likely results in mood disorders such as anxiety. Interestingly, most if not all of the inputs and receptor expression patterns that distinguish CCK cells from PV cells are strongly implicated in anxiety for reviews see Freund, ; Freund and Katona, This group of interneurons is the most diverse both morphologically and functionally.
Dendritic Inhibitory cells are present in many different parts of the nervous system, including the cerebellum where stellate cells target Purkinje cell dendrites and Golgi cells innervate granule cell dendrites , the olfactory bulb where inhibitory granule cells and periglomerular cells establish dendro-dendritic synapses onto excitatory mitral cells , and all areas of the cerebral cortex. In the neocortex, a large variety of Dendritic Inhibitory interneurons have been described for review see Markram et al.
These include Martinotti cells, which target mainly the apical tuft region of pyramidal cells, contain the neuropeptide somatostatin and are thus to some extent similar to O-LM cells of the hippocampus, as described below , double bouquet cells and bipolar cells, which target mostly basal dendrites, as well as bitufted cells and neurogliaform cells. However, the precise functions of these neocortical cell types have been difficult to identify.
The functionally relevant classification based on afferent and efferent connectivity is easier to determine in the hippocampus, where afferent pathways and cellular compartments are confined to different laminae. Distinct types of dendritic interneurons have evolved to control glutamatergic inputs of principal cells from different sources. In general, each interneuron type can be more effectively driven by a preferred stimulus; this diversity of activation thus broadens the operating range of the neuronal circuits.
In this context, understanding the roles of each individual interneuron type is a critical first step in elucidating the functionality of the whole neuronal circuit. This Research Topic will focus on how local interneurons modulate sensory signal processing and highlight the roles that interneurons play in physiological or pathological circuitries.
Contributors may submit: 1. Reviews highlighting the significant features of inhibitory neurons within their circuits; 2. We observed that control mice were indeed able to discriminate between the two textures, as they spent significantly more time exploring the novel textured object compared to the textured object they had already encountered Fig.
In fact, the time spent investigating the novel texture was significantly lower in the mutant compared to controls Fig. It is worthy to mention that mice from both groups considered for analysis spent similar amounts of time exploring the textures during the testing phase, confirming that differences in novel texture exploration were due to the ability to discriminate and not a by-product of the amount of time spent exploring the objects exploration time: 9.
These behavioral data thus indicate that a disruption of FSI-oligodendroglia interactions, inducing severe FSI myelination defects during development, also leads to deficient whisker-dependent discrimination of a new texture in the adult. Note that control mice preferentially explore the novel object while mutants do not discriminate between the two objects. For a long time, it has been known that myelination is important to speed up the conduction of action potentials.
However, myelination patterns vary according to CNS regions and it is unknown why some axons are ensheathed by myelin while others are not. This report focuses on the impact of FSI myelination on the morphology and function of FSI in a specific inhibitory circuit of layer IV of the barrel cortex, which is critical for the sensory gating process Our results demonstrate that, beyond conduction, FSI myelination shapes the morphology of the proximal axon, the high frequency of action potential discharges and the connectivity of these interneurons with excitatory neurons.
These deleterious effects on FSI are then associated with impairments in whisker-dependent discrimination, i. They also display shorter internodes and nodes than non-GABAergic neurons 7 , 9. Here, we found that an early disruption of FSI-oligodendroglia interactions results in a defective myelination, which displayed almost twice longer nodes and internodes and were associated with aberrant modifications of proximal axon morphology. Hence these results point to a critical role of FSI myelination in guiding proximal axon morphology.
Conversely, a recent report shows that FSI morphology is important to guide myelination The authors show that the enlargement of FSI size by genetic manipulations increases axonal myelination, while a decreased cell size leads to a reduced myelination Therefore, it exists an interdependency between FSI morphology and myelination that reveals a previously unexpected and intimate interplay between FSI and oligodendroglia which is critical for maintaining both the architecture of FSI axons and a correct myelination pattern.
This interdependency probably already exists early on during postnatal development as FSIs synaptically contact OPCs during the first two postnatal weeks 8 , Interestingly, the reduced morphological complexity of differentiating OLs in the mutant also suggests that the inactivation of OPC GABAergic synapses mainly affects the transition from a progenitor to an OL state.
In turn, we observed an aberrant axon morphology and myelination of FSI. The idea that interneurons and oligodendroglia are reciprocal partners during development is reinforced by recent data showing that 1 both cell types are born from progenitors expressing similar transcription factors and lying in the same germinal regions 8 , 38 , 39 ; 2 lineage-related interneurons and OPCs are initially over-produced and then significantly demised at early postnatal stages 8 , 38 , 40 ; 3 surviving lineage-related interneurons and oligodendroglia form anatomical and functional clusters at postnatal stages 8 , and 4 migrating interneurons secrete the cytokine fraktaline which promotes oligodendrogenesis via the fraktaline receptor CX3CR1 expressed in OPCs Interestingly, different axon geometries and myelin distributions at proximal axon regions also shape action potential discharges allowing intrinsic excitability of neurons to be tuned 20 , 23 , Compared to pyramidal neurons whose action potentials are initiated far from the axon hillock 43 , the generation of action potentials in FSI occurs very close to the soma However, it is probably not a coincidence that FSI myelination occurs in the proximal part of the axon where action potentials are initiated and efficiently propagated towards smaller axon branches and synaptic termini 7 , 9.
In fact, myelination defects of FSI caused a significant reduction in their high firing frequency without modifying other properties such as input resistance, resting potential, AHP, action potential amplitudes and fast spike kinetics. This lack of changes in intrinsic electrophysiological properties makes major modifications in protein and channel expression at the AIS and nodes of Ranvier in the mutant rather unlikely.
Future studies, however, will be needed to determine the molecular identity and distribution of different proteins and ion channels in myelinated FSI axons both in normal and pathological conditions. The slow conduction could thus be the main cause of the reduced firing frequency of FSI in the mutant.
Although there is a relationship between the lengths of internodes and nodes and conduction speed, node lengths appear to play a critical role in tuning action potential propagation 21 which may explain the reduced conduction velocity of FSI in the mutant. In summary, the specific proximal axon morphology and myelination pattern of FSI mainly impacts the high rate and reliable propagation of action potentials rather than the spike form.
Although myelin distribution is restricted to the first part of FSI axons, our results show that this myelination pattern is required to optimize the fast-spiking phenotype and the high temporal precision of action potential discharges of FSI. Therefore, these properties do not rely solely on FSI intrinsic properties.
Thus, if myelination profiles are also altered in other neurons in the mutant, these changes do not appear to significantly interfere with their physiological properties. Recently, a study demonstrated that a lack of compact myelin correlates with a reduced GABAergic synaptic transmission in Purkinje cells of the cerebellum Diminished cerebellar myelination following neonatal hypoxia also decreases GABAergic synaptic activity of migrating white matter interneurons These reports suggest that, beyond conduction, axonal myelination influences synaptic neurotransmission.
In line with this, we found that the inactivation of FSI—OPC synapses during early postnatal development resulted in myelination defects of FSI that were associated with a strong reduction of FSI-SSC connectivity in mature local circuits confined within the barrel structure.
While the feedforward inhibition of SSCs was significantly reduced in the mutant upon electrical thalamic stimulation at P30, our paired recordings revealed a lack of FSI-SSC connectivity within a single barrel and in the area of the myelinated part of the FSI axon i. Distal FSI e. FSI in adjacent barrels or layers as well as some somatostatin-expressing interneurons 48 may thus participate in the remaining IPSCs evoked by electrical thalamic stimulation at P30 in the mutant.
P10 , this connectivity in the mutant did not follow the developmental increase normally occurring in conjunction with myelination 19 , Hence, our results point to a crucial role of FSI myelination in the maturation of synaptic connectivity of these interneurons with nearby SSCs within barrels. In the barrel cortex, the feedforward inhibition of FSI in layer IV circuits is key to avoid redundant recurrent thalamocortical excitation of SSCs and maintain the dynamic balance between excitation and inhibition necessary to optimize sensory responses Indeed, the synchronous and fast discharge of FSI, immediately following thalamocortical excitation, generates a feedforward release of GABA within layer IV barrel structures that shortens the duration of SSC excitation By suppressing most of the excitability of SSCs, this feedforward inhibitory circuit filters irrelevant information and optimizes sensory processing, allowing for a reliable and precise response to relevant stimuli 12 , Our findings show that FSI dysfunctions caused by myelination defects impact the functioning of these interneurons in a cortical neuronal circuit that is critical for sensory information processing during whisker-related behaviors.
Notably, FSI constitutes a primary source of inhibition in the neocortex and provide a robust synaptic input which inhibits the activity of excitatory neurons with high temporal precision, shaping cortical circuit dynamics during specific brain states and different behavioral contexts.
Beyond conduction, our data demonstrate that FSI myelination appears as a key factor in regulating the inhibition of local cortical networks.
Nevertheless, myelin anomalies of these interneurons cause dramatic changes in firing frequency, inhibitory circuit function, and behavior. Interestingly, FSI constitutes a recurrent locus of dysfunctions in neurodevelopmental diseases such as schizophrenia. Notably, the synchronization of neuronal ensembles in the gamma range frequency, which largely depends on FSI activity 50 , is commonly altered in this disease. Considering our demonstration of the important role of FSI myelination in regulating the function of FSI, it is thus possible that FSI myelination defects alter local cortical circuit oscillations in vivo which, in turn, contribute to cognitive deficits observed in this disease 5 , Animals were genotyped by PCR using primers specific for the different alleles and Cre expression was induced from P3 to P5 by daily intraperitoneal injections of 0.
Both female and male were indiscriminately used at different postnatal stages from P10 to P Patch-clamp recordings were performed at RT using an extracellular solution containing in mM : NaCl, 2. Biocytin-loaded OPCs and differentiating OLs for morphological analysis and postsynaptic SSCs during paired recordings were recorded with a CsCl-based intracellular solution containing in mM : CsCl, 5 4-aminopyridine, 10 tetraethylammonium chloride, 0.
Recordings were made without series resistance R s compensation. Acquisition was obtained using Multiclamp B and pClamp Firing properties, evoked postsynaptic currents and paired recordings were analyzed off-line using pClamp Mice were perfused with phosphate buffer saline PBS followed by 0.
Primary antibodies used for immunohistochemistry were rabbit polyclonal anti-Olig2 ; ref. OP80, Millipore , rabbit polyclonal anti-NG2 ; ref. MAB, Merck. Slices with primary antibodies were washed three times in PBS and incubated in secondary polyclonal antibodies. We used goat anti-rabbit DyLight ref. A, Thermofisher Scientific , goat anti-mouse Alexa Fluor ref. A, Thermofisher Scientific , goat anti-mouse DyLight ref. To prevent border effects in countings, cells that were at the boundaries of the analyzed volume were not considered in three of the six sides of the cube if somata were not fully inside.
Cell density was obtained by dividing the number of cells by the cube volume. Primary antibodies used for immunohistochemistry were either rabbit polyclonal anti-PV ; ref. PV, Swant or rabbit polyclonal anti-Caspr ; ref.
AB, Abcam. Slices with primary antibodies were washed three times in PBS and incubated in secondary antibodies coupled, respectively, to goat anti-rabbit Alexa Fluor and goat anti-rat Alexa Fluor as well as in conjugated streptavidin—Alexa Fluor ; ref.
Biocytin-loaded FSI was randomly selected during recordings. To avoid any biased during analysis, a successful axon labeling was the only criterion to keep the cell for further morphological analysis. FSI axon morphology was determined from 3D reconstructions where only clearly interconnected branches were considered.
Although this choice left aside the most distal and thinnest processes, it ensured that no small dendritic branch was included by error in the two groups. This procedure also reduces possible variations due to slicing, cell loading, and depth of recorded cells in slices, ensuring a more accurate comparison between groups. For node length analysis, we selected nodes found between two consecutive myelinated internodes flanked by two Caspr-labeled paranodes.
A maximum intensity projection was generated from sections including Caspr labeling for a single node up to four interleaved confocal slices of 0. The size of the node was then calculated measuring the distance between the half maximum intensity for each paranode To characterize the complexity of the ramifications of layer IV OL lineage cells in relation to the distance from the soma, we performed Sholl analysis with ImageJ software using confocal z-stack images of biocytin-loaded cells optical sections of 0.
Briefly, the model was implemented from Model C of Richardson et al. It contains an axon divided into three compartments i. They are multipolar, just like motor neurons. In the brain, the distinction between types of neurons is much more complex. Certainly, there are brain neurons involved in sensory processing — like those in visual or auditory cortex — and others involved in motor processing — like those in the cerebellum or motor cortex.
However, within any of these sensory or motor regions, there are tens or even hundreds of different types of neurons. In fact, researchers are still trying to devise a way to neatly classify the huge variety of neurons that exist in the brain.
Looking at which neurotransmitter a neuron uses is one way that could be a useful for classifying neurons. However, within categories we can find further distinctions. Some GABA neurons, for example, send their axon mostly to the cell bodies of other neurons; others prefer to target the dendrites.
Furthermore, these different neurons have different electrical properties, different shapes, different genes expressed, different projection patterns and receive different inputs.
In other words, a particular combination of features is one way of defining a neuron type. The thought is that a single neuron type should perform the same function, or suite of functions, within the brain.
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