Inhibitory Neurons: Keeping the Brain’s Traffic in Check

Imagine that you’re driving down a road undeterred, no red lights or stop signs to slow you down. While that may seem like a very exciting idea, it is obviously very dangerous, since our roads are not all parallel, but interconnected in a number of different ways. For traffic to go smoothly in all directions, we have stop signs, red lights, speed bumps and police cars to make sure no accidents occur. In much the same way, our brain has a mechanism to keep the excitation in check. Information in the brain flows via excitatory neurons that have properties depending on their anatomical location. For example, a neuron in the visual cortex will respond to visual stimuli, and a neuron in the auditory cortex will respond to auditory stimuli. Since excitation cannot go on forever, we have to make sure it slows down or stops whenever required. This is known as inhibition. Inhibition is as important as excitation, if not more so. The neurons that perform this function are known as inhibitory neurons, and they have the special property of making sure our brain functions smoothly and is accident-free.

When activated, inhibitory neurons release the neurotransmitter GABA, which is known to hyperpolarize the postsynaptic neurons, i.e. it makes the membrane potential more negative, making it harder for the neuron to reach the threshold to fire an action potential, thereby causing ‘inhibition’. Most often, inhibitory neurons are also called GABAergic neurons for that reason. Although they constitute only 20-25% of all neurons in the cortex, they are strikingly diverse, with different morphologies, sizes, intrinsic properties, connectivity patterns, and protein expression. Based on their molecular properties, a significant effort has been made in recent years to classify them into subgroups [1]. Let’s explore a few of the major inhibitory neuron subtypes:

Parvalbumin (PV) type of inhibitory interneurons:

Named after the characteristic protein they carry – parvalbumin, a regulatory calcium binding protein – these interneurons comprise of 40% of interneuron subpopulation.

Location: Layers 2 to 6 of the cortex.

Morphology: Basket cells. They have an extensive branching of their processes that gives them a basket-like appearance [2].

Characteristic features: They are fast spiking neurons. They have fast channels that grant them short recovery periods, i.e. they can fire action potentials at a high rate [3]. They receive inputs from both excitatory neurons in the cortex as well as the thalamus. At least in layer 4, the major recipient layer of the cortex, they are the main source of fast feed forward inhibition onto neighboring excitatory neurons, where, upon receiving inputs from the thalamus, they get activated and now inhibit their neighboring excitatory neurons in the forward direction.

Somatostatin (SOM) type of inhibitory neurons:

Named after a characteristic peptide hormone they carry – somatostatin, involved in neurotransmission and cell proliferation – these interneurons are the second most abundant in the cortex. In upper layers they are 25% of the inhibitory neuron population, while in deeper layers they constitute almost 50% of the total inhibitory neuron population.

Location: Mostly layers 2 to 6, with their density increasing with depth.

Morphology: Martinotti cells (named after Carlo Martinotti who discovered these). They possess ovoid cell bodies; axons decorated with spiny boutons and beaded dendrites.

Characteristic features: A very striking feature of SOM neurons is that their axons go all the way up to layer 1, forming collaterals and spreading horizontally over a very large area. SOM axons in general seem to target distal dendrites of the neurons they connect with [2] to provide a delayed response to stimuli [4].

5HT3aR expressing neurons:

Named after the characteristic ionotropic serotonin receptor 5HT3a these express, the 5HTaR interneurons are the third largest group of inhibitory neurons [5]. Being the most recent group to be characterized, these include two major subgroups: (1) Vasoactive intestinal peptide (VIP) neurons and (2) Reelin expressing neurons.

Vasoactive intestinal peptide (VIP) neurons

They are the least abundant type of inhibitory neurons (~12%),

Location: Their proportion is the highest in layer 2/3.

Morphology: They are usually bipolar cells in morphology, meaning that they have two axons originating from the cell body, each going in the opposite direction.

Characteristic features: Not much is known about their functionality of VIP, though recently, studies are attributing a disinhibitory role to these neurons i.e. an inhibition of other inhibitory neurons, thereby relieving the overall inhibition of excitatory neurons.

Reelin expressing neurons

Location: Found mostly in layer 1.

Morphology: Neurogliaform i.e. they are neurons that morphologically show glia-like processes.

In addition to the three major groups of inhibitory neurons mentioned above, there are a number of other smaller subgroups with various morphologies and molecular properties.

One cannot emphasize enough on the importance of GABAergic neurons. There are numerous diseases that occur if inhibitory neuron function is altered or if there is inhibitory neuron loss. One example is epilepsy.  Epilepsy is nothing but excitation going unchecked, producing excitotoxicity that gives rise to seizures. In addition to being gatekeepers of excitation, inhibitory neuron activity is very important in refining specific properties of excitatory neurons.  For example, a very simple property of neurons in the visual cortex is that of orientation selectivity, where a neuron responds to a bar of light oriented in a particular angle.  Without inhibitory neurons, PV in particular, this property would actually be very weak, and our visual system may not function as well as it does.

Despite their smaller proportion, cortical inhibitory neurons play very essential roles in modulating cortical activity. Just like the traffic lights and stop signs, our brain has all these different types of inhibitory neurons that come in various shapes and sizes that allow them to play distinct roles in shaping how we perceive and interact with the world around us.

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Written by Leena A. Ibrahim. Images by Jooyeun Lee.

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References:

1. Rudy B., Gordon Fishell, SooHyun Lee & Jens Hjerling-Leffler (2010). Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons, Developmental Neurobiology, 71 (1) 45-61. DOI: http://dx.doi.org/10.1002/dneu.20853

2. Markram H., Maria Toledo-Rodriguez, Yun Wang, Anirudh Gupta, Gilad Silberberg & Caizhi Wu (2004). Interneurons of the neocortical inhibitory system, Nature Reviews Neuroscience, 5 (10) 793-807. DOI: http://dx.doi.org/10.1038/nrn1519

3. Rudy B. & Chris J. McBain (2001). Kv3 channels: voltage-gated K channels designed for high-frequency repetitive firing, Trends in Neurosciences, 24 (9) 517-526. DOI: http://dx.doi.org/10.1016/s0166-2236(00)01892-0

4. Ma W.P., B.-h. Liu, Y.-t. Li, Z. Josh Huang, L. I. Zhang & H. W. Tao (2010). Visual Representations by Cortical Somatostatin Inhibitory Neurons–Selective But with Weak and Delayed Responses, Journal of Neuroscience, 30 (43) 14371-14379. DOI:http://dx.doi.org/10.1523/jneurosci.3248-10.2010

5. Lee S., J. Hjerling-Leffler, E. Zagha, G. Fishell & B. Rudy (2010). The Largest Group of Superficial Neocortical GABAergic Interneurons Expresses Ionotropic Serotonin Receptors, Journal of Neuroscience, 30 (50) 16796-16808. DOI:http://dx.doi.org/10.1523/jneurosci.1869-10.2010