ABSTRACT
The neuronal population of the subthalamic nucleus (STN) has the ability to prolong incoming cortical excitation. This could result from intra-STN feedback excitation. The combination of inducible genetic fate mapping techniques with in vitro targeted patch-clamp recordings, allowed identifying a new type of STN neurons that possess a highly collateralized intrinsic axon. The time window of birth dates was found to be narrow (E10.5-E14.5) with very few STN neurons born at E10.5 or E14.5. The fate mapped E11.5-12.5 STN neuronal population included 20% of neurons with profuse axonal branching inside the nucleus and a dendritic arbor that differed from that of STN neurons without local axon collaterals. They had intrinsic electrophysiological properties and in particular, the ability to generate plateau potentials, similar to that of STN neurons without local axon collaterals and more generally to that of classically described STN neurons. This suggests that a subpopulation of STN neurons forms a local glutamatergic network, which together with plateau potentials, allow amplification of hyperdirect cortical inputs and synchronization of the STN neuronal population.
Subject(s)
Axons/physiology , Neurons/cytology , Subthalamic Nucleus/cytology , Action Potentials/physiology , Animals , Animals, Newborn , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Biotin/analogs & derivatives , Biotin/metabolism , Calcium-Binding Proteins/metabolism , Embryo, Mammalian , Female , In Vitro Techniques , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Membrane Potentials/physiology , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/physiology , Patch-Clamp Techniques , Subthalamic Nucleus/embryology , Subthalamic Nucleus/growth & developmentABSTRACT
The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)-P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease.
Subject(s)
Gene Expression Regulation, Developmental/physiology , Neurons/physiology , Receptors, N-Methyl-D-Aspartate/metabolism , Subthalamic Nucleus/cytology , Action Potentials/drug effects , Action Potentials/genetics , Animals , Animals, Newborn , Dendrites/metabolism , Dendrites/ultrastructure , Excitatory Amino Acid Agents/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , Female , Gene Expression Regulation, Developmental/drug effects , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/ultrastructure , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/genetics , Subthalamic Nucleus/growth & developmentABSTRACT
The subthalamic nucleus (STN) is a crucial node in the basal ganglia. Clinical success in targeting the STN for deep brain stimulation in Parkinson's disease patients has prompted increased interest in understanding STN biology. In this report, we discuss recent evidence for transcription factor mediated regulation of STN development. We also review STN developmental neurobiology and known patterns of gene expression in the developing and mature STN.
Subject(s)
Gene Expression Regulation, Developmental/physiology , Gene Expression , Subthalamic Nucleus/metabolism , Transcription Factors , Animals , Brain Diseases/metabolism , Humans , Neural Networks, Computer , Neural Pathways/anatomy & histology , Neural Pathways/physiology , Neurons/physiology , Subthalamic Nucleus/cytology , Subthalamic Nucleus/growth & development , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Using standard immunohistochemical procedures, we investigated the changes in the expression of ionotropic glutamate receptor (GluR) subunits, GluRl, GluR5/6/7, and NMDAR1, in the subthalamic nucleus of developing rats. The general sequence of development for each subunit was the same. At early postnatal ages, there was dense neuropil staining and cellular clustering which progressed to decreased neuropil staining and an even distribution of conspicuous cells in the later postnatal ages and in the adult. GluR5/6/7 displayed the earliest maturation, while GluR1 exhibited the slowest maturation. These morphological changes suggest a different time course for the functionality of GluR subtypes in the developing subthalamic nucleus. Correlative electrophysiological studies demonstrated functional GluRs as early as 16 days of age. All neurons tested displayed robust responses to kainate and N-methyl-D-aspartate, and these responses were modulated by dopamine.
