Layer 1 (L1) neurons, in particular Cajal–Retzius (CR) cells are among the earliest generated neurons in the neocortex. However, their role and that of L1 GABAergic interneurons in the establishment of an early cortical microcircuit are still poorly understood. Thus, the morphology of whole-cell recorded and biocytin-filled CR cells was investigated in postnatal day (P) 7–11 old CXCR4-EGFP mice where CR cells can be easily identified by their fluorescent appearance. Confocal-, light- and subsequent electron microscopy was performed to investigate their developmental regulation, morphology, synaptic input–output relationships and electrophysiological properties. CR cells reached their peak in occurrence between P4 to P7 and from thereon declined to almost complete disappearance at P14 by undergoing selective cell death through apoptosis. CR cells formed a dense and long-range horizontal network in layer 1 with a remarkable high density of synaptic boutons along their axons. They received dense GABAergic and non-GABAergic synaptic input and in turn provided synaptic output preferentially with spines or shafts of terminal tuft dendrites of pyramidal neurons. Interestingly, no dye-coupling between CR cells with other cortical neurons was observed as reported for other species, however, biocytin-labeling of individual CR cells leads to co-staining of L1 end foot astrocytes. Electrophysiologically, CR cells are characterized by a high input resistance and a characteristic firing pattern. Increasing depolarizing currents lead to action potential of decreasing amplitude and increasing half width, often terminated by a depolarization block. The presence of membrane excitability, the high density of CR cells in layer 1, their long-range horizontal axonal projection together with a high density of synaptic boutons and their synaptic input–output relationship suggest that they are an integral part of an early cortical network important not only in layer 1 but also for the establishment and formation of the cortical column.
SUMMARY Abnormal subthalamic nucleus (STN) activity is linked to impaired movement in Parkinson’s disease (PD). The autonomous firing of STN neurons, which contributes to their tonic excitation of the extrastriatal basal ganglia and shapes their integration of synaptic input, is downregulated in PD models. Using electrophysiological, chemogenetic, genetic, and optical approaches, we find that chemogenetic activation of indirect pathway striatopallidal neurons downregulates intrinsic STN activity in normal mice but this effect is occluded in Parkinsonian mice. Loss of autonomous spiking in PD mice is prevented by STN N-methyl-D-aspartate receptor (NMDAR) knockdown and reversed by reactive oxygen species breakdown or K ATP channel inhibition. Chemogenetic activation of hM3D(Gq) in STN neurons in Parkinsonian mice rescues their intrinsic activity, modifies their synaptic integration, and ameliorates motor dysfunction. Together these data argue that in PD mice increased indirect pathway activity leads to disinhibition of the STN, which triggers maladaptive NMDAR-dependent downregulation of autonomous firing.
Cajal-Retzius cells are thought to play an important role for cortical development, and receive primarily spontaneous GABAergic input mediated by GABAA receptors. However, neither the effects of synaptically-released GABA on their excitability nor the cellular source(s) of spontaneous GABAergic currents have been yet determined. By directly recording electrophysiological responses from identified Cajal-Retzius cells of the CXCR4-EGFP mouse, we show that GABAergic input can trigger supra-threshold responses, and that the pharmacological activation of mGlu1α receptors with the group I agonist DHPG powerfully increases the frequency of spontaneous GABAergic currents. These effects appeared mediated by a network mechanism, because responses to DHPG were completely prevented both by surgical disconnection of layer I from lower layers and by exposure of slices to TTX. We propose that the cellular source underlying the observed effect of DHPG are layer I-targeting Martinotti-like interneurons, which we show express functional group I mGluRs and respond to DHPG with supra-threshold depolarization already at early developmental stages. In conclusion, our work suggests that conditions of enhanced glutamate release may be critical at early developmental stages for the recruitment of an mGlu1α-dependent micro-circuit, which then leads to the activation of Cajal-Retzius cells.
Excitatory transmission within hippocampal area CA3 stems from three major glutamatergic pathways: the perforant path formed by axons of layer II stellate cells in the entorhinal cortex, the mossy fiber axons originating from the dentate gyrus granule cells, and the recurrent axon collaterals of CA3 pyramidal cells. The synaptic communication of each of these pathways is modulated by metabotropic glutamate receptors that fine-tune the signal by affecting both the timing and strength of the connection. Within area CA3 of the hippocampus, group I mGluRs (mGluR1 and mGluR5) are expressed postsynaptically, whereas group II (mGluR2 and mGluR3) and III mGluRs (mGluR4, mGluR7, and mGluR8) are expressed presynaptically. Receptors from each group have been demonstrated to be required for different forms of pre- and postsynaptic long-term plasticity and also have been implicated in regulating short-term plasticity. A recent observation has demonstrated that a presynaptically expressed mGluR can affect the timing of action potentials elicited in the postsynaptic target. Interestingly, mGluRs can be distributed in a target-specific manner, such that synaptic input from one presynaptic neuron can be modulated by different receptors at each of its postsynaptic targets. Consequently, mGluRs provide a mechanism for synaptic specialization of glutamatergic transmission in the hippocampus. This review will highlight the variability in mGluR modulation of excitatory transmission within area CA3 with an emphasis on how these receptors contribute to the strength and timing of network activity within pyramidal cells and interneurons.
The hippocampal mossy fiber (MF) pathway originates from the dentate gyrus granule cells and provides a powerful excitatory synaptic drive to neurons in the dentate gyrus hilus and area CA3. Much of the early work on the MF pathway focused on its electrophysiological properties, and ability to drive CA3 pyramidal cell activity. Over the last ten years, however, a new focus on the synaptic interaction between granule cells with inhibitory interneurons has emerged. These data have revealed an immense heterogeneity of long-term plasticity at MF synapses on various interneuron targets. Interestingly, these studies also indicate that the mechanisms of MF long-term plasticity in some interneuron subtypes may be more similar to pyramidal cells than previously appreciated. In this review, we first define the synapse types at each of the interneuron targets based on the receptors present. We then describe the different forms of long-term plasticity observed, and the mechanisms underlying each form as they are currently understood. Finally we highlight various open questions surrounding MF long-term plasticity in interneurons, focusing specifically on the induction and maintenance of LTP, and what the functional impact of persistent changes in efficacy at MF -interneuron synapses might be on the emergent properties of the inhibitory network dynamics in area CA3.
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