Electrophysiology and Optogenetics used to reveal innovation in the developing hippocampus

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Electrophysiology and Optogenetics used to reveal innovation in the developing hippocampus

Brain development is a complicated and amazing process, where cells migrate and grow into the necessary connections for brain function. Cajal-Retzius cells are a class of neurons believed to play a critical role during cortical development. They are a major source of reelin, a large glycoprotein that plays an essential role in neuronal migration and cortical layer formation.

Little is known about the innovation of Cajal-Retzius cells or their precise computational function within the hippocampal network. Now, new research from Giulia Quattrocolo and Gianmaria Maccaferri at Northwestern University provides new insight.

Using electrophysiology and optogenetic methods, with a Scientifica SliceScope upright microscope, the researchers have found evidence that GABAergic input into hippocampal Cajal-Retzius cells is provided by neurogliaform and oriens lacunosum-moleculare interneurons.

Using interneuron – Cajal-Retzius cell paired recordings, they established that GABA, released by hippocampal striatum lacunosum-moleculare local interneurons (neurogliaform-like cells), generate small amplitude and slow kinetic responses on Cajal-Retzius cells. These responses were entirely mediated by GABAA receptors.

Cajal-Retzius cells also exhibit larger-amplitude and kinetically faster events that occur spontaneously on Cajal-Retzius cells. This suggests that another type of interneuron is responsible for the faster, higher amplitude activity. They therefore tested the hypothesis that oriens lacunosum-moleculare (O-LM) interneurons contribute to the postsynaptic currents with larger amplitudes and faster kinetics.

This time, they were unable to record oriens lacunosum-moleculare (O-LM) - Cajal-Retzius paired cell unitary events, so they devised an alternative method to test their hypothesis, using a combination of optogenetics and electrophysiology.

O-LM cells express the neuropeptide Sst, so the group used Sst-IRES-Cre mice to optically stimulate just the O-LM cell population, within the hippocampus. They found that light stimulation of stratum lacunosum-moleculare with a short pulse of light revealed evoked high amplitude, kinetically fast postsynaptic currents in Cajal-Retzius cells. These results suggested O-LM interneurons make up at least part of the larger amplitude and kinetically faster events seen in Cajal-Retzius cells. Further evidence for this conclusion was provided by recording the synaptic responses produced by electrical stimulation of stratum oriens with single and multiple pulses in the constant presence of ionotropic glutamate receptor blockers. This stimulation generated GABAergic post-synaptic responses on Cajal-Retzius cells similar to those obtained with optogenetic stimulation.

Also the group found that exposing slices to the group 1 mGluR agonist DHPG in the presence of antagonists of ionotropic glutamate receptors increased the frequency of synaptic events in O-LM (which expresses high levels of group 1 mGluR). These events in turn increased frequency of postsynaptic currents observed in Cajal-Retzius cells, but only when stratum oriens was left connected to stratum lacunosum-moleculare.

Together the data strongly suggests that Cajal-Retzius cells receive direct GABAergic input from both neuogliaform and O-LM interneurons, although not necessarily exclusively. Also, these two sources of cellular inputs produce different forms of response. For further discussion of the functional dichotomy of these responses and the possible computational functions of Cajal-Retzius cells in the development of the hippocampal network, view the original paper.

Paper reference:
Giulia Quattrocolo and Gianmaria Maccaferri, "Novel GABAergic Circuits Mediating Excitation/Inhibition of Caja-Retzius Cells in the Developing Hippocampus". The Journal of Neuroscience (2013) 33(13):5486-5498 DOI:10.1523/JNEUROSCIENCE.5680-12.2013


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