Hippocampal subfield differentiation

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There has been a lot written in recent years about interneuron diversity. Excitatory interneurons exist, but more often than not interneurons produce and release the major inhibitory neurotransmitter, GABA. Interneurons are locally connected, and they can control local circuit oscillations and excitability. There are about a zillion different types of GABAergic interneuron based in morphology, physiology, and molecular content. All this interneuron diversity has got me wondering about the diversity of another major neuron class, the excitatory pyramidal neuron. Look, here comes one now:

They are called pyramidal because that’s how you can loosely describe the shape of their cell body. They usually have an apical dendrite that comes out of the top. The one pictured is bifurcating where the arrow is pointing. They have basilar dendrites that come out the sides near the bottom, and they have an axon that comes straight out the bottom (indicated by an arrowhead in this picture). This particular model is a CA3 pyramidal neuron, found in the CA3 subfield of the hippocampus. The hippocampus is made up of the dentate gyrus (DG) and the Ammon’s horn (cornu ammonis, CA). These are two curving rows of cell bodies all lined up so their dendrites and axons are pointing the same directions. The DG curves rather sharply and makes something like a V or a crest. The CA fields together form a milder curve that still comes out something like a C. The bottom portion of the CA “C” interlocks with the DG, so you could draw something like a S to get both subregions of the hippocampus. Here’s a link to a picture if my description is confusing. The CA1 field covers mostly the top arc or the “C”, while the CA3 field is from more like 6 to 10 on the C clockface.

If you just look at a picture of the hippocampus, the division seems completely arbitary. CA1? CA3? And what happened to CA2? There actually are meaningful differences between the subfields though and it’s not a smooth gradient. Functionally, one important distinction is connectivity. The CA3 pyramidal neurons are much more highly interconnected than CA1 pyramidal neurons. This allows them to chatter with each other and do computations locally. Some have suggested this ‘recurrent network’ property of CA3 places it in a role as a pattern completion computer. Morphologically, CA3 cells are bigger than CA1 cells. And this is where my knowledge sort of runs out and I don’t know where to look. I’d like to know the rest of the differences between CA3 and CA1 cells. I would like to know whether one of the two is more like some class of neocortical pyramidal cell. I have one last place to check, my Hippocampus book, but I don’t have it with me right now.

I did find this paper though, by Tole et al., that shows that the CA fields are specified early in development (~ embryonic day 15 in mice), and that they don’t need extrinisic cues to develop properly. These brave folks managed to dissect out embryonic hippocampi (which are tiny already) and then subdivide them into even smaller “presumptive CA fields” and grow them up. The CA1 and CA3 fields still gain the proper cell morphology and cell-type markers without any help from outside sources. They also found that the differentiation of these cell-types starts at the ends of the CA layer and works its way in, so eventually there is a hole of undifferentiation in between the CA1 and CA3 specified cells. The two finally meet at about embryonic (post-conception) day 19.5 just around the date of birth. This explains CA2 as well. CA2 is where the two differentiation signals intermingle and produce some CA3-type and some CA1-type cells. The markers used in this paper are not terribly informative about function, but could perhaps be used to derive a line of mice with different colored CA3 and CA1 cells that we could grab and do genomics on. Having good specific markers for these cell-types would, in general, assist in the development of transgenic technologies to piece apart subregion contributions to hippocampal funciton. I wonder if CA3 and CA1 pyramidal cell-types can be any further subdivided or if we already understood the full-range of hippocampal excitatory diversity.

Update:The Spruston and McBain chapter in The Hippocampus Book is a treasure trove for this kind of stuff. It’s going to require a whole new post. Also, Tole and Grove didn’t stop publishing in 1997, so I will have to look into their more recent work.


  1. Ed Lein has used gene expression to demarcate boundaries between subregions.

  2. thanx chairmanK. thanks for the answer down on the dendrite post too.

  3. It’s kind of off topic, but did any of you know that there is a developmental stage of neurons in which GABA(A) receptors are actually excitatory?. The switch occurs when a particular potassium/chloride cotransporter starts being expressed, so that the Cl- gradient reverses direction to its “mature” state in which [Cl-] is greater outside. This changes the equilibrium potential of Cl- from depolarizing to hyperpolarizing. I even remember reading about a theory that, in some types of epilepsy, certain GABA synapses might spontaneously revert to being excitatory, causing the excitation/inhibition imbalance. 
    I first learned about this about a month ago, I believe when reading one of the references cited by a paper linked to on here. I had never heard about that before, and meant to post something, but I was in the middle of studying for finals and trying to get some stuff done for my grad school apps, so I never got around to it. If one of you knows and wants to post something about this, go ahead, otherwise I’ll post a link to some papers.

  4. i’ve heard of something similar in the spinal cord. a friend needed an explanation for why his behavioral results were coming out the same with a GABA-A antagonist and a NMDA antagonist. but i don’t know the specifics about which kinds of transporters and all that jazz.