Article

Postsynaptic mechanisms govern the differential excitation of cortical neurons by thalamic inputs.

Neurobiology Section, Division of Biology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0634, USA.
Journal of Neuroscience (Impact Factor: 6.91). 08/2009; 29(28):9127-36. DOI: 10.1523/JNEUROSCI.5971-08.2009
Source: PubMed

ABSTRACT Thalamocortical (TC) afferents relay sensory input to the cortex by making synapses onto both excitatory regular-spiking principal cells (RS cells) and inhibitory fast-spiking interneurons (FS cells). This divergence plays a crucial role in coordinating excitation with inhibition during the earliest steps of somatosensory processing in the cortex. Although the same TC afferents contact both FS and RS cells, FS cells receive larger and faster excitatory inputs from individual TC afferents. Here, we show that this larger thalamic excitation of FS cells occurs via GluR2-lacking AMPA receptors (AMPARs), and results from a fourfold larger quantal amplitude compared with the thalamic inputs onto RS cells. Thalamic afferents also activate NMDA receptors (NMDARs) at synapses onto both cells types, yet RS cell NMDAR currents are slower and pass more current at physiological membrane potentials. Because of these synaptic specializations, GluR2-lacking AMPARs selectively maintain feedforward inhibition of RS cells, whereas NMDARs contribute to the spiking of RS cells and hence to cortical recurrent excitation. Thus, thalamic afferent activity diverges into two routes that rely on unique complements of postsynaptic AMPARs and NMDARs to orchestrate the dynamic balance of excitation and inhibition as sensory input enters the cortex.

0 Bookmarks
 · 
64 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia may involve hypofunction of NMDA receptor (NMDAR)-mediated signaling, and alterations in parvalbumin-positive fast-spiking (FS) GABA neurons that may cause abnormal gamma oscillations. It was recently hypothesized that prefrontal cortex (PFC) FS neuron activity is highly dependent on NMDAR activation and that, consequently, FS neuron dysfunction in schizophrenia is secondary to NMDAR hypofunction. However, NMDARs are abundant in synapses onto PFC pyramidal neurons; thus, a key question is whether FS neuron or pyramidal cell activation is more dependent on NMDARs. We examined the AMPAR and NMDAR contribution to synaptic activation of FS neurons and pyramidal cells in the PFC of adult mice. In FS neurons, EPSCs had fast decay and weak NMDAR contribution, whereas in pyramidal cells, EPSCs were significantly prolonged by NMDAR-mediated currents. Moreover, the AMPAR/NMDAR EPSC ratio was higher in FS cells. NMDAR antagonists decreased EPSPs and EPSP-spike coupling more strongly in pyramidal cells than in FS neurons, showing that FS neuron activation is less NMDAR dependent than pyramidal cell excitation. The precise EPSP-spike coupling produced by fast-decaying EPSCs in FS cells may be important for network mechanisms of gamma oscillations based on feedback inhibition. To test this possibility, we used simulations in a computational network of reciprocally connected FS neurons and pyramidal cells and found that brief AMPAR-mediated FS neuron activation is crucial to synchronize, via feedback inhibition, pyramidal cells in the gamma frequency band. Our results raise interesting questions about the mechanisms that might link NMDAR hypofunction to alterations of FS neurons in schizophrenia.
    Journal of Neuroscience 01/2011; 31(1):142-56. · 6.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A highly diverse population of neocortical GABAergic inhibitory interneurons has been implicated in multiple functions in information processing within cortical circuits. The diversity of cortical interneurons is determined during development and primarily depends on their embryonic origins either from the medial (MGE) or the caudal (CGE) ganglionic eminences. Although MGE-derived parvalbumin (PV)- or somatostatin (SST)-expressing interneurons are well characterized, less is known about the other types of cortical GABAergic interneurons, especially those of CGE lineage, because of the lack of specific neuronal markers for these interneuron subtypes. Using a bacterial artificial chromosome transgenic mouse line, we show that, in the somatosensory cortex of the mouse, the serotonin 5-hydroxytryptamine 3A (5-HT(3A)) receptor, the only ionotropic serotonergic receptor, is expressed in most, if not all, neocortical GABAergic interneurons that do not express PV or SST. Genetic fate mapping and neurochemical profile demonstrate that 5-HT(3A)R-expressing neurons include the entire spectrum of CGE-derived interneurons. We report that, in addition to serotonergic responsiveness via 5-HT(3A)Rs, acetylcholine also depolarizes 5-HT(3A)R-expressing neurons via nicotinic receptors. 5-HT(3A)R-expressing neurons in thalamocortical (TC) recipient areas receive weak but direct monosynaptic inputs from the thalamus. TC input depolarizes a subset of TC-recipient 5-HT(3A)R neurons as strongly as fast-spiking cells, in part because of their high input resistance. Hence, fast modulation of serotonergic and cholinergic transmission may influence cortical activity through an enhancement of GABAergic synaptic transmission from 5-HT(3A)R-expressing neurons during sensory process depending on different behavioral states.
    Journal of Neuroscience 12/2010; 30(50):16796-808. · 6.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pioneering studies in the middle of the twentieth century revealed substantial diversity among mammalian chemical synapses and led to a widely accepted classification of synapse type on the basis of neurotransmitter molecule identity. Subsequently, powerful new physiological, genetic and structural methods have enabled the discovery of much deeper functional and molecular diversity within each traditional neurotransmitter type. Today, this deep diversity continues to pose both daunting challenges and exciting new opportunities for neuroscience. Our growing understanding of deep synapse diversity may transform how we think about and study neural circuit development, structure and function.
    Nature Reviews Neuroscience 05/2012; 13(6):365-79. · 31.38 Impact Factor

Full-text

View
0 Downloads
Available from