Carole E. Landisman

Small Clusters of Electrically Coupled Neurons Generate Synchronous Rhythms in the Thalamic Reticular Nucleus

The inhibitory neurons of the thalamic reticular nucleus (TRN) contribute to the generation of widespread oscillations in the thalamocortical system. Some TRN neurons are interconnected by electrical synapses, and here we tested the possibility that electrical synapses mediate rhythmic synchrony in juvenile rats. Both the incidence and strength of electrical coupling between pairs of TRN neurons were a steep function of intersomatic distance, and coupling was absent at distances >40 μm. Presynaptic spike bursts evoked much larger electrical postsynaptic potentials than did single presynaptic spikes. Activation of metabotropic glutamate receptors (mGluRs) with a bath-applied agonist or an endogenous ligand released during tetanic stimulation induced robust rhythms of the subthreshold membrane potential, with a mean frequency of ∼10 Hz. In the absence of fast chemical synaptic transmission, subthreshold rhythms and the action potentials that they evoked were well synchronized between closely spaced, electrically coupled pairs; rhythms in noncoupled cells were not synchronized. The results suggest that electrical synapses can coordinate spindle-frequency rhythms among small clusters of mGluR-activated TRN cells.

Long-Term Modulation of Electrical Synapses in the Mammalian Thalamus

Electrical synapses are common between inhibitory neurons in the mammalian thalamus and neocortex. Synaptic modulation, which allows flexibility of communication between neurons, has been studied extensively at chemical synapses, but modulation of electrical synapses in the mammalian brain has barely been examined. We found that the activation of metabotropic glutamate receptors, via endogenous neurotransmitter or by agonist, causes long-term reduction of electrical synapse strength between the inhibitory neurons of the rat thalamic reticular nucleus.

Activity-Dependent Long-Term Depression of Electrical Synapses

Paired bursting in coupled neurons depresses electrical synapses while their asymmetry increases after unidirectional use. Use-dependent forms of synaptic plasticity have been extensively characterized at chemical synapses, but a relationship between natural activity and strength at electrical synapses remains elusive. The thalamic reticular nucleus (TRN), a brain area rich in gap-junctional (electrical) synapses, regulates cortical attention to the sensory surround and participates in shifts between arousal states; plasticity of electrical synapses may be a key mechanism underlying these processes. We observed long-term depression resulting from coordinated burst firing in pairs of coupled TRN neurons. Changes in gap-junctional communication were asymmetrical, indicating that regulation of connectivity depends on the direction of use. Modification of electrical synapses resulting from activity in coupled neurons is likely to be a widespread and powerful mechanism for dynamic reorganization of electrically coupled neuronal networks.

VPM and PoM Nuclei of the Rat Somatosensory Thalamus: Intrinsic Neuronal Properties and Corticothalamic Feedback

Sensory information originating in individual whisker follicles ascends through focused projections to the brainstem, then to the ventral posteromedial nucleus (VPM) of the thalamus, and finally into barrels of the primary somatosensory cortex (S1). By contrast, the posteromedial complex (PoM) of the thalamus receives more diffuse sensory projections from the brainstem and projects to the interbarrel septa of S1. Both VPM and PoM receive abundant corticothalamic projections from S1. Using a thalamocortical slice preparation, we characterized differences in intrinsic neuronal properties and in responses to corticothalamic feedback in neurons of VPM and PoM. Due to the plane of the slice, the majority of our observed responses came from activation of layer VI because most or all of the layer V axons terminating in PoM are cut. We found that VPM neurons exhibit higher firing rates than PoM neurons when stimulated with injected current. Stimulation of corticothalamic fibers evoked monosynaptic excitation, disynaptic inhibition, or a combination of the two in both nuclei. A few differences in the feedback responses emerged: purely excitatory postsynaptic potentials (EPSPs) in VPM were smaller and facilitated more than those in PoM, and only the EPSPs in VPM had a strong NMDA component. For both nuclei, some of the feedback responses were purely disynaptic inhibitory postsynaptic potentials (IPSPs) from the thalamic reticular nucleus (TRN). This was due to EPSP failures within VPM and PoM combined with greater reliability of S1-originating synapses onto TRN. These findings suggest that despite the exclusively excitatory nature of corticothalamic fibers, activation of cortex can trigger excitation or inhibition in thalamic relay neurons.

Connexon connexions in the thalamocortical system.

Electrical synapses are composed of gap junction channels that interconnect neurons. They occur throughout the mammalian brain, although this has been appreciated only recently. Gap junction channels, which are made of proteins called connexins, allow ionic current and small organic molecules to pass directly between cells, usually with symmetrical ease. Here we review evidence that electrical synapses are a major feature of the inhibitory circuitry in the thalamocortical system. In the neocortex, pairs of neighboring inhibitory interneurons are often electrically coupled, and these electrical connections are remarkably specific. To date, there is evidence that five distinct subtypes of inhibitory interneurons in the cortex make electrical interconnections selectively with interneurons of the same subtype. Excitatory neurons (i.e., pyramidal and spiny stellate cells) of the mature cortex do not appear to make electrical synapses. Within the thalamus, electrical coupling is observed in the reticular nucleus, which is composed entirely of GABAergic neurons. Some pairs of inhibitory neurons in the cortex and reticular thalamus have mixed synaptic connections: chemical (GABAergic) inhibitory synapses operating in parallel with electrical synapses. Inhibitory neurons of the thalamus and cortex express the gap junction protein connexin 36 (C x 36), and knocking out its gene abolishes nearly all of their electrical synapses. The electrical synapses of the thalamocortical system are strong enough to mediate robust interactions between inhibitory neurons. When pairs or groups of electrically coupled cells are excited by synaptic input, receptor agonists, or injected current, they typically display strong synchrony of both subthreshold voltage fluctuations and spikes. For example, activating metabotropic glutamate receptors on coupled pairs of cortical interneurons or on thalamic reticular neurons can induce rhythmic action potentials that are synchronized with millisecond precision. Electrical synapses offer a uniquely fast, bidirectional mechanism for coordinating local neural activity. Their widespread distribution in the thalamocortical system suggests that they serve myriad functions. We are far from a complete understanding of those functions, but recent experiments suggest that electrical synapses help to coordinate the temporal and spatial features of various forms of neural activity.

State-dependent modulation of gap junction signaling by the persistent sodium current.

Thalamic neurons fluctuate between two states: a hyperpolarized state associated with burst firing and sleep spindles, and a depolarized state associated with tonic firing and rapid, reliable information transmission between the sensory periphery and cortex. The thalamic reticular nucleus (TRN) plays a central role in thalamocortical processing by providing feed-forward and feedback inhibition to thalamic relay cells; TRN cells participate in the generation of sleep spindles, and have been suggested to focus the neural “searchlight” of attention. The mechanisms underlying synchrony in the TRN during different behavioral states are largely unknown. TRN cells are densely interconnected by electrical synapses. Here we show that activation of the persistent sodium current (INaP) by depolarization causes up to fourfold changes in electrical synaptic efficacy between TRN neurons. We further show that amplification of electrical synaptic responses strongly enhances tonic spike synchrony but, surprisingly, does not affect burst coordination. We use a Hodgkin–Huxley model to gain insight into the differences between the effects of burstlets, spikelets, and amplification on burst and spike times.

Activation of Group I and Group II Metabotropic Glutamate Receptors Causes LTD and LTP of Electrical Synapses in the Rat Thalamic Reticular Nucleus

Compared with the extensive characterization of chemical synaptic plasticity, electrical synaptic plasticity remains poorly understood. Electrical synapses are strong and prevalent among the GABAergic neurons of the rodent thalamic reticular nucleus. Using paired whole-cell recordings, we show that activation of Group I metabotropic glutamate receptors (mGluRs) induces long-term depression of electrical synapses. Conversely, activation of the Group II mGluR, mGluR3, induces long-term potentiation of electrical synapses. By testing downstream targets, we show that modifications induced by both mGluR groups converge on the same signaling cascade—adenylyl cyclase to cAMP to protein kinase A—but with opposing effects. Furthermore, the magnitude of modification is inversely correlated to baseline coupling strength. Thus, electrical synapses, like their chemical counterparts, undergo both strengthening and weakening forms of plasticity, which should play a significant role in thalamocortical function.

Developmental changes in somatostatin-positive interneurons in a freeze-lesion model of epilepsy.

Somatostatin-expressing (SS) cells are inhibitory interneurons critical to the regulation of excitability in the cerebral cortex. It has been suggested in several animal models of epilepsy that the activity of these neurons reduces the occurrence and strength of epileptiform activity. The physiological properties of SS cells further support these hypotheses. Freeze lesions of neonatal rats serve as a model of human polymicrogyria, which is often characterized by severe seizures. Here we investigate the effects of neonatal freeze lesions on SS-expressing neurons by measuring their densities in control and lesioned hemispheres at two ages. We found that in late juveniles (P30-P32), SS-expressing neurons were depleted by 20% in areas adjacent to the freeze lesion, but at an earlier developmental age (P14-15), there was no significant loss. Since the deficit in SS-expressing neurons occurs well after the onset of epileptiform activity (P12-P18), we conclude that the death of these interneurons does not initiate hyperexcitability in this model.

Bursts modify electrical synaptic strength

Changes in synaptic strength resulting from neuronal activity have been described in great detail for chemical synapses, but the relationship between natural forms of activity and the strength of electrical synapses had previously not been investigated. The thalamic reticular nucleus (TRN), a brain area rich in gap junctional (electrical) synapses, regulates cortical attention, initiates sleep spindles, and participates in shifts between states of arousal. Plasticity of electrical synapses in the TRN may be a key mechanism underlying these processes. Recently, we demonstrated a novel activity-dependent form of long-term depression of electrical synapses in the TRN (Haas et al., 2011). Here we provide an overview of those findings and discuss them in broader context. Because gap junctional proteins are widely expressed in the mammalian brain, modification of synaptic strength is likely to be a widespread and powerful mechanism at electrical synapses throughout the brain.

Thalamus: Organization and Function (Vol. 1), Experimental and Clinical Aspects (Vol. 2)

Abstract edited by M. Steriade, E.G. Jones and D.A. McCormick, Elsevier, 1997.