Interneurons in the neocortex of the brain are small, locally projecting GABAergic cells with a vast collection of anatomical and physiological properties. Their diversity was believed to be crucial for regulating numerous operations in the neocortex. An analysis of the current theories and concepts surrounding interneuron diversity was undertaken, and the findings presented here.
The neocortex acts as the centre for highest nervous function in vertebrates, responsible for cognition, perception, & action. Reflecting these roles, neocortical neurons are selective for several different kinds of stimuli . These neurons, rather than being randomly distributed in the cortical sheet, are arranged in layers (I-VI) each of which connects to different cortical/subcortical regions . Most neocortical neurons (70-80%) are excitatory pyramidal neurons (otherwise termed 'principal cells') with relatively stereotyped anatomical, physiological, and molecular properties [4, 7]. The remaining ~20-30% are a select population of locally projecting neurons termed interneurons (INs) with diverse physiological, morphological, and molecular characteristics [4, 7]. Despite their diversity, there are common features amongst them which distinguish interneurons from principal cells. Firstly, the presence of aspiny dendrites on most mature inhibitory INs. Second, the fact that they are able to receive both inhibitory and excitatory synapses onto their somata . Third, interneuron axons and dendritic arbours are restricted to the neocortex. And finally, different types of inhibitory INs are capable of targeting different sub-domains of neurons (dendritic regions, soma, or axons) . Excitatory INs (e.g. the spiny stellate cell - SSC) make use of glutamate as a neurotransmitter, whereas the actions of inhibitory INs encompass the release of the inhibitory neurotransmitter GABA (g-aminobutyric acid) and co-release of neuropeptides such as somatostatin, neuropeptide Y, vasoactive intestinal polypeptide, and cholecystokinin .
Diversity of Neocortical Interneurons
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Due to the great variety of interneuronal dissimilarities (morphological/electrophysiological/neurochemical) it seems plausible to state that any meaningful classification scheme of neocortical interneurons should be based only on function. As such, in a functional classification the chief characteristics are the input-output properties (i.e. the identity of afferents that drive any specific cell type and the sites where these cells exert their inhibitory effects) .
Interneurons innervate different cell types only in proportion to their occurrence at any site, thus, they synapse principally on the most abundant cell type which, in the neocortex, are local principal cells. However, there do exist special INs that preferentially target other interneurons rather than principal cells; subsets of INs containing the calcium binding protein Calretinin, or the neuropeptide vasoactive intestinal polypeptide, were shown to synapse predominantly on other GABAergic cells, and were therefore termed Interneuron-Selective interneurons (IS cells) - this represents the first major division in the classification scheme. These IS cells are relatively scarce and are ideally suited to synchronize inhibition in the brain (both in the neocortex and hippocampus) .
The next major branch of the classification scheme of INs is determined by the particular principal cell compartment which they target. Interneurons that target principal cell dendrites (the Dendritic Inhibitory cells e.g. Martinotti cells, Double Bouquet cells, Bipolar cells, Bitufted cells, and Neurogliaform cells) are designed to manage the efficiency and plasticity of excitatory inputs to principal cells. Whilst INs innervating somata, proximal dendrites, or axon initial segments (the Perisomatic Inhibitory cells e.g. Chandelier cells, and Basket cells) are specialized to control the output from large principal cell populations; they act to rhythmically synchronize principal cell activity at theta and gamma frequencies .
The final major division in the classification scheme encompasses the long-range group of interneurons. INs of this group have axon trees that span two or more anatomical brain regions, these axons provide fast communication between innervated areas. Since this group of inhibitory cells projects over large distances, the term 'interneuron' is not strictly accurate. Nevertheless, for historical reasons all GABAergic cells in the cerebral cortex are referred to as 'inhibitory interneurons'[22, 23].
Interneurons are endowed with cell-specific (intrinsic and synaptic) physiological properties due to another feature that differs amongst INs, namely, their molecular identity and density of voltage-gated ion channels in their cell membranes, and in the molecular composition of their input/output synapses. For instance, parvalbumin-containing basket cells express voltage-gated potassium channels which contribute to the "fast-spiking" nature of these neurons, thus allowing them to respond rapidly to synaptic input, all-the-while sustaining high-frequency spiking activity in response to a strong input . Also, some neuronal classes show distinct peaks (termed "resonances") in their impedance profiles (the differential dependence of the sub-threshold voltage response on the frequency of stimulation) at certain frequencies, which may contribute to their different involvement in the generation of network oscillations in multiple frequency bands .
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Additionally, both excitatory synapses onto INs and the inhibitory synapses formed by INs on local principal cells have physiological properties that dependent upon interneuron class. Input/output synapses may differ in the amplitude and/or kinetics of the postsynaptic response. They also differ in the type of plasticity (facilitation/depression) that the INs express, thus leading to the involvement of various IN types in shaping network activity, which itself is dependent upon the rate and temporal firing pattern in pyramidal neurons, as well as the interneurons involved .
Inhibition is mediated by multiple receptors
The concept of inhibition involves the interruption/blocking of activity, and restriction of activity patterns. In the cortex, an inhibitory action is achieved through release of inhibitory neurotransmitter from axon terminals of INs onto their synaptic targets, thus these inhibitory forces compete with (or counteract) excitatory forces brought about by principal cells. Thereby, maintaining the dynamics of the neuronal network. As such, it can be said that INs provide the crucial autonomy and independence to nearby principal cells, whose functional diversity can be further enhanced through the domain-specific actions of GABAergic INs. Furthermore, the opposing excitation and inhibition actions usually bring about network and membrane oscillations which provide temporal coordination of messages transmitted by pyramidal neurons .
As mentioned earlier, inhibition in higher brain regions (neocortex/hippocampus) is mediated by g-aminobutyric acid. GABA released from pre-synaptic terminals activates three types of receptors, called GABA receptors (GABARs) type A, B, and C . GABAARs are ligand-gated ion channels permeable to chloride ions and, to a much lesser extent, to bicarbonate ions. This finding explains why the synaptic reversal potential is slightly more positive that the chloride equilibrium potential (calculated from the Nernst equation). Whereas postsynaptic GABABRs are heptahelical receptors coupled to inwardly rectifying potassium ion channel via guanoine triphosphate (GTP)-binding proteins. Lastly, GABACRs are ligand-gated chloride ion channels comprised of rho subunits, and are primarily expressed in the retina .
These inhibitory transmitter receptors are located on the postsynaptic neurons. And during postsynaptic inhibition their activation leads to either a change in membrane potential (of the postsynaptic neuron), or an increase in postsynaptic conductance, or perhaps even a combination of both these outcomes - ultimately inhibiting action potential generation in the postsynaptic neuron. Such inhibition can be termed 'phasic' (short-lasting, generated by activation of GABAARs following action potentials in a presynaptic IN) or 'tonic' (a form of long-lasting inhibition - GABA in extracellular space activates GABAA conductance). Additionally, a long-lasting form of inhibition is mediated by non-synchronized spontaneous release of GABA onto functionally specialized GABAARs [15, 16].
Finally, we can distinguish 'hyperpolarizing' and 'shunting' inhibition; Since GABAAR-mediated inhibition makes use of chloride channels, the concentration gradient of chloride ions across the cell membrane determines the nature of the inhibitory effect. And if the synaptic reversal potential of GABAAR-mediated currents (which varies amongst cell types) falls below the resting potential, inhibition is said to be hyperpolarizing. Conversely, if the synaptic reversal potential reaches a level between the resting potential and the action potential threshold, GABAergic synapses are said to have shunting effects, so named because synaptic conductance will tend to short-circuit currents generated at nearby excitatory synapses. However, under the conditions described earlier, effects of shunting inhibition consist of two, more complex, temporal phases. In the first phase, conductance dominates, leading to inhibition of the postsynaptic cell. In the second phase, conductance has decayed but membrane potential remains depolarized. In addition, the effects of hunting inhibition can be said to be activity-dependent, however, the result is that input resistance is high and membrane potential is shifted towards the action potential threshold; excitability is increased [17,18]
Feed-forward, Feedback, and other forms of Inhibition
The simplest combination in a network involves an excitatory element (principal cell) and an inhibitory element (interneuron), the firing pattern will depend on the precise wiring scheme. In a feedback inhibitory system, increased firing of the principal cell amplifies IN neurotransmitter release frequency which, in turn, decreases principal cell output; negative (inhibitory) feedback provides stability (through a regulatory mechanism) .
In a feed-forward inhibitory circuit, increased interneuronal discharge leads to decreased principal cell activity. Here, simple pairing of excitation and inhibition elements substantially increases the temporal precision of firing. In other words, feed-forward inhibition dampens the effect of afferent excitation. Any departure from basic feedback/feed-forward mechanisms inevitably increases the complexity of firing patterns in the participating cells, and makes it far mor difficult to predict [19, 20].
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Lateral inhibition (an extension of feedback inhibition) occurs when principal cell activation recruits an IN which, in turn, suppresses the activity of adjacent pyramidal neurons. In other words, lateral inhibitionÂ provides autonomy of neurons by suppressing the activity of neighbouring neurons (also referred to as a 'winner take all' situation). In general terms, the inhibitory interneuron system plays a critical role in determining the non-linearity and functional complexity of cortical networks .
Spatio-Temporal coordination in Cortical networks
Neuronal networks accomplish basic functions such as pattern completion and pattern separation, these relate to processes of integration and differentiation. A network of inhibitory connections allows for functional isolation of competing cell assemblies and adjacent excitatory neurons. Further, excitatory paths can be re-routed by the traffic-controlling ability of coordinated interneuron groups .
The temporal and spatial distribution of inhibition affects specific firing patterns of principal cells in a network. An outcome of this is that a network could produce various output patterns in response to the same input, depending on the particular state of inhibition. In addition, coordinated inhibition ensures the recruitment of precise numbers of neurons in the right temporal window by means of excitatory activity . Principal cells acting alone could not achieve this level of cortical processing. Furthermore, the rivalry between excitatory and inhibitory neurons ensures the stability of neuronal firing rates over extended cortical regions, yet still allows for fast dramatic increases of local excitability, a necessity for communication and modifying network connections .
Despite being maximally sensitized to external confounding influences, neuronal networks with multiple levels of excitatory and inhibitory constituents are resilient systems, capable of absorbing large external effects without undergoing functional breakdown. However, on those occasions where these interactions are altered in some way, there is the possibility of resultant brain diseases/ Interneuronopathies, epilepsy, and various forms of psychiatric diseases (including autism, schizophrenia, and anxiety disorders) .
Functions of Neocortical Interneurons
Possibly the oldest and simplest idea, with regard to neocortical neurons is that INs act to maintain physiological activity levels in the brain, and in doing so they regulate excitation in recurrent cortical networks . This concept has been widely accepted, given the fact that there is evidence of changes in excitation levels being accompanied by a subsequent alteration in the overall level(s) of inhibition. However, transient imbalances between excitation and inhibition can also be induced. In the neocortex as well as in the hippocampus, changes in the level of interneuronal activity have been seen to follow behaviourally significant novel experiences, and perhaps even contribute to induction of plastic changes that are induced by such learning events. As mentioned earlier, INs make a vital contribution to the generation of network oscillations, and synchronize the principal cell activity during oscillatory and transient brain states [12, 13].
Perisomatic interneurons in particular are thought to be central for the generation of rapid population rhythms; this can possibly be achieved through greater gamma oscillation frequency. Interaction between excitatory and inhibitory neuronal populations can also potentially generate some forms of gamma oscillation. Even so, pure IN networks, connected via GABAergic synapses (and even often throughÂ electrical synapsesÂ formed by gap junctions), are also known to be capable of generating rhythmic, synchronous (inhibitory) activity in the gamma frequency range. Such inputs, generated by interneuron populations can in turn effectively synchronize the activity of local principal cell groups which should act to enhance the efficacy of information transmission by increasing the likelihood of coincident spiking - an effective trigger of action potential generation in downstream neurons .
In addition to providing a temporal framework for principal cell activity and maintaining homeostasis, INs probably serve more direct roles in neocortical computations. At the network level, both feedback and feed-forward inhibition act to decrease the number of concurrently active pyramidal neurons, working towards the production of sparse representations - thought to be beneficial for both long-term and sensory memory. Also, feedback inhibition systems introduce direct competition amongst the members of any local principal cell population, whereby an increase in the activity/firing rate of one cell results in the reduced activity of its neighbours. There is a point to invoking this form of competition, and that is to adopt a simple yet effective means of noise suppression which, if complemented by local recurrent excitation, regulates selection between any putative (competing) inputs. In fact, such competition is thought to even induce implementation of complex computations such as working memory and decision-making in the neocortex [12, 13, 14]
To summarize, the inhibitory interneuronal network, when coupled to principal cells populations, provides the crucial flexibility for complex cortical computations. Opposing forces, such as excitation and inhibition, compete to give rise to rhythmic behaviour. Thus, the provision of a rhythm-based timing mechanism to principal neurons is one of the most important roles of INs. Once a collective oscillatory pattern arises, it constrains the timing freedom of its members thereby decreasing the likelihood for principal cells to discharge; thus, principal cells become synchronized. Synchronization by oscillation occurs at multiple time scale (tens of milliseconds to seconds). The duration of the oscillation subsequently determines the length of informational computations that can be transmitted, as well as the spatial extent of the involved neuronal populations .
As such, through the induction of oscillations inhibition can create multiple temporal and spatial organization in the neocortex. Among the IN classes, Basket cells play a particularly important role in the generation of network oscillations; they are highly active during gamma activity and initiate action potentials which are precisely phase-locked to the oscillations. Computer analysis has shown that network models of mutually connected basket interneurons can generate synchronized oscillations if exposed to a tonic excitatory drive. The high abundance, locally extensive axonal arborization, and fast signaling properties of parvalbumin-expressing basket cells are very suitable for the generation of fast network oscillations [24, 
Perhaps the best way to explain my understanding of this entire concept is in a simple analogy; the interneuron network acts as a clock, providing a time signal input to excitatory pyramidal neuron assemblies (throughout the brain). But how is it that interneuronal activation can synchronize principal cell populations over large distances? Perhaps this manner of widespread synchrony is achieved by region-spanning axon collaterals of principal cells or even by the family of long-range interneurons. The latter solution can perhaps provide the necessary fast conductance for synchronizing distantly operating oscillators and allow for consistent timing of large numbers of principal cells that are not connected directly to each other. Understanding the molecular (synaptic) mechanisms of inhibition and deduction of how key processes contribute to the multifarious dynamics of neuronal networks must remain an important objective for future research.