Thalamic Interneurons Research Articles

Mechanism of an Intrinsic Oscillation in Rat Geniculate Interneurons.

Depolarizing current injections produced a rhythmic bursting of action potentials - a bursting oscillation - in a set of local interneurons in the lateral geniculate nucleus (LGN) of rats. The current dynamics underlying this firing pattern have not been determined, though this cell type constitutes an important cellular component of thalamocortical circuitry, and contributes to both pathologic and non-pathologic brain states. We thus investigated the source of the bursting oscillation using pharmacological manipulations in LGN slices in vitro and in silico. 1. Selective blockade of calcium channel subtypes revealed that high-threshold calcium currents and contributed strongly to the oscillation. 2. Increased extracellular K+ concentration (decreased K+currents) eliminated the oscillation. 3. Selective blockade of K+ channel subtypes demonstrated that the calcium-sensitive potassium current ( ) was of primary importance. A morphologically simplified, multicompartment model of the thalamic interneuron characterized the oscillation as follows: 1. The low-threshold calcium current provided the strong initial burst characteristic of the oscillation. 2. Alternating fluxes through high-threshold calcium channels and then provided the continuing oscillation's burst and interburst periods respectively. This interplay between and contrasts with the current dynamics underlying oscillations in thalamocortical and reticularis neurons, which primarily involve and , or and respectively. These findings thus point to a novel electrophysiological mechanism for generating intrinsic oscillations in a major thalamic cell type. Because local interneurons can sculpt the behavior of thalamocortical circuits, these results suggest new targets for the manipulation of ascending thalamocortical network activity.

The type of inhibition provided by thalamic interneurons alters the input selectivity of thalamocortical neurons

A fundamental problem in neuroscience is how neurons select for their many inputs. A common assumption is that a neuron's selectivity is largely explained by differences in excitatory synaptic input weightings. Here we describe another solution to this important problem. We show that within the first order visual thalamus, the type of inhibition provided by thalamic interneurons has the potential to alter the input selectivity of thalamocortical neurons. To do this, we developed conductance injection protocols to compare how different types of synchronous and asynchronous GABA release influence thalamocortical excitability in response to realistic patterns of retinal ganglion cell input. We show that the asynchronous GABA release associated with tonic inhibition is particularly efficient at maintaining information content, ensuring that thalamocortical neurons can distinguish between their inputs. We propose a model where alterations in GABA release properties results in rapid changes in input selectivity without requiring structural changes in the network.

Sonic hedgehog-dependent recruitment of GABAergic interneurons into the developing visual thalamus.

Axons of retinal ganglion cells (RGCs) play critical roles in the development of inhibitory circuits in visual thalamus. We previously reported that RGC axons signal astrocytes to induce the expression of fibroblast growth factor 15 (FGF15), a motogen required for GABAergic interneuron migration into visual thalamus. However, how retinal axons induce thalamic astrocytes to generate Fgf15 and influence interneuron migration remains unknown. Here, we demonstrate that impairing RGC activity had little impact on interneuron recruitment into mouse visual thalamus. Instead, our data show that retinal-derived sonic hedgehog (SHH) is essential for interneuron recruitment. Specifically, we show that thalamus-projecting RGCs express SHH and thalamic astrocytes generate downstream components of SHH signaling. Deletion of RGC-derived SHH leads to a significant decrease in Fgf15 expression, as well as in the percentage of interneurons recruited into visual thalamus. Overall, our findings identify a morphogen-dependent neuron-astrocyte signaling mechanism essential for the migration of thalamic interneurons.

Dual midbrain and forebrain origins of thalamic inhibitory interneurons.

The ubiquitous presence of inhibitory interneurons in the thalamus of primates contrasts with the sparsity of interneurons reported in mice. Here, we identify a larger than expected complexity and distribution of interneurons across the mouse thalamus, where all thalamic interneurons can be traced back to two developmental programmes: one specified in the midbrain and the other in the forebrain. Interneurons migrate to functionally distinct thalamocortical nuclei depending on their origin: the abundant, midbrain-derived class populates the first and higher order sensory thalamus while the rarer, forebrain-generated class is restricted to some higher order associative regions. We also observe that markers for the midbrain-born class are abundantly expressed throughout the thalamus of the New World monkey marmoset. These data therefore reveal that, despite the broad variability in interneuron density across mammalian species, the blueprint of the ontogenetic organisation of thalamic interneurons of larger-brained mammals exists and can be studied in mice.

Fluctuations of sensorimotor processing in migraine: a controlled longitudinal study of beta event related desynchronization

BackgroundThe migraine brain seems to undergo cyclic fluctuations of sensory processing. For instance, during the preictal phase, migraineurs experience symptoms and signs of altered pain perception as well as other well-known premonitory CNS-symptoms. In the present study we measured EEG-activation to non-painful motor and sensorimotor tasks in the different phases of the migraine cycle by longitudinal measurements of beta event related desynchronization (beta-ERD).MethodsWe recorded electroencephalography (EEG) of 41 migraine patients and 31 healthy controls. Each subject underwent three EEG recordings on three different days with classification of each EEG recording according to the actual migraine phase. During each recording, subjects performed one motor and one sensorimotor task with the flexion-extension movement of the right wrist.ResultsMigraine patients had significantly increased beta-ERD and higher baseline beta power at the contralateral C3 electrode overlying the primary sensorimotor cortex in the preictal phase compared to the interictal phase. We found no significant differences in beta-ERD or baseline beta power between interictal migraineurs and controls.ConclusionIncreased preictal baseline beta activity may reflect a decrease in pre-activation in the sensorimotor cortex. Altered pre-activation may lead to changes in thresholds for inhibitory responses and increased beta-ERD response, possibly reflecting a generally increased preictal cortical responsivity in migraine. Cyclic fluctuations in the activity of second- and third-order afferent somatosensory neurons, and their associated cortical and/or thalamic interneurons, may accordingly also be a central part of the migraine pathophysiology.

Developmental Remodeling of Thalamic Interneurons Requires Retinal Signaling.

The dorsal lateral geniculate nucleus (dLGN) of the mouse is a model system to study the development of thalamic circuitry. Most studies focus on relay neurons of dLGN, yet little is known about the development of the other principal cell type, intrinsic interneurons. Here we examined whether the structure and function of interneurons relies on retinal signaling. We took a loss-of-function approach and crossed GAD67-GFP mice, which express GFP in dLGN interneurons, with math5 nulls (math5-/-), mutants that lack retinal ganglion cells and retinofugal projections. In vitro recordings and 3-D reconstructions of biocytin-filled interneurons at different postnatal ages showed their development is a multistaged process involving migration, arbor remodeling, and synapse formation. Arbor remodeling begins during the second postnatal week, after migration to and dispersion within dLGN is complete. This phase includes a period of exuberant branching where arbors grow in number, complexity, and field size. Such growth is followed by branch pruning and stabilization, as interneurons adopt a bipolar architecture. The absence of retinal signaling disrupts this process. The math5-/- interneurons fail to branch and prune, and instead maintain a simple, sparse architecture. To test how such defects influence connectivity with dLGN relay neurons, we used DHPG [(RS)-3,5-dihydroxyphenylglycine], the mGluR1,5 agonist that targets F2 terminals. This led to substantial increases in IPSC activity among WT relay neurons but had little impact in math5-/- mice. Together, these data suggest that retinal signaling is needed to support the arbor elaboration and synaptic connectivity of dLGN interneurons.SIGNIFICANCE STATEMENT Presently, our understanding about the development of the dorsal lateral geniculate nucleus is limited to circuits involving excitatory thalamocortical relay neurons. Here we show that the other principal cell type, intrinsic interneurons, has a multistaged developmental plan that relies on retinal innervation. These findings indicate that signaling from the periphery guides the maturation of interneurons and the establishment of inhibitory thalamic circuits.

Uncertainpy: A Python Toolbox for Uncertainty Quantification and Sensitivity Analysis in Computational Neuroscience

Computational models in neuroscience typically contain many parameters that are poorly constrained by experimental data. Uncertainty quantification and sensitivity analysis provide rigorous procedures to quantify how the model output depends on this parameter uncertainty. Unfortunately, the application of such methods is not yet standard within the field of neuroscience. Here we present Uncertainpy, an open-source Python toolbox, tailored to perform uncertainty quantification and sensitivity analysis of neuroscience models. Uncertainpy aims to make it quick and easy to get started with uncertainty analysis, without any need for detailed prior knowledge. The toolbox allows uncertainty quantification and sensitivity analysis to be performed on already existing models without needing to modify the model equations or model implementation. Uncertainpy bases its analysis on polynomial chaos expansions, which are more efficient than the more standard Monte-Carlo based approaches. Uncertainpy is tailored for neuroscience applications by its built-in capability for calculating characteristic features in the model output. The toolbox does not merely perform a point-to-point comparison of the “raw” model output (e.g., membrane voltage traces), but can also calculate the uncertainty and sensitivity of salient model response features such as spike timing, action potential width, average interspike interval, and other features relevant for various neural and neural network models. Uncertainpy comes with several common models and features built in, and including custom models and new features is easy. The aim of the current paper is to present Uncertainpy to the neuroscience community in a user-oriented manner. To demonstrate its broad applicability, we perform an uncertainty quantification and sensitivity analysis of three case studies relevant for neuroscience: the original Hodgkin-Huxley point-neuron model for action potential generation, a multi-compartmental model of a thalamic interneuron implemented in the NEURON simulator, and a sparsely connected recurrent network model implemented in the NEST simulator.

Rethinking schizophrenia through the lens of evolution: shedding light on the enigma

Schizophrenia refers to a complex psychiatric illness characterized by the heterogenic presence of positive, negative and cognitive symptoms occurring in all human societies. The fact that the disorder lacks a unifying neuropathology, presents a decreased fecundity of the affected individuals and has a cross-culturally stable incidence rate, makes it necessary for an evolutionary explanation that fully accounts for the preservation of “schizophrenic genes” in the global human genepool, explaining the potential sex differences and the heterogeneous cognitive symptomatology of the disorder and is consistent with the neuropsychological, developmental and evolutionary findings regarding the human brain. Here we proposed a new evolutionary framework for schizophrenia that is consistent with findings presented in different dimensions, considering the disorder as a form of brain functioning that allows us to adapt to the environment and, ultimately, maintain the survival of the species. We focus on the epigenetic regulation of thalamic interneurons as a major player involved in the development of the clinical picture characteristic of schizophrenia.

Thalamocortical Projection Neuron and Interneuron Numbers in the Visual Thalamic Nuclei of the Adult C57BL/6 Mouse.

A key parameter to constrain predictive, bottom-up circuit models of a given brain domain is the number and position of the neuronal populations involved. These include not only the neurons whose bodies reside within the domain, but also the neurons in distant regions that innervate the domain. The mouse visual cortex receives its main subcortical input from the dorsal lateral geniculate nucleus (dLGN) and the lateral posterior (LP) complex of the thalamus. The latter consists of three different nuclei: lateral posterior lateral (LPL), lateral posterior medial rostral (LPMR), and lateral posterior medial caudal (LPMC), each exhibiting specific patterns of connections with the various visual cortical areas. Here, we have determined the number of thalamocortical projection neurons and interneurons in the LP complex and dLGN of the adult C57BL/6 male mouse. We combined Nissl staining and histochemical and immunolabeling methods for consistently delineating nuclei borders, and applied unbiased stereological cell counting methods. Thalamic interneurons were identified using GABA immunolabeling. The C57BL/6 dLGN contains ∼21,200 neurons, while LP complex contains ∼31,000 total neurons. The dLGN and LP are the only nuclei of the mouse dorsal thalamus containing substantial numbers GABA-immunoreactive interneurons. These interneurons, however, are scarcer than previously estimated; they are 5.6% of dLGN neurons and just 1.9% of the LP neurons. It can be thus inferred that the dLGN contains ∼20,000 and the LP complex ∼30,400 thalamocortical projection neurons (∼12,000 in LPL, 15,200 in LPMR, and 4,200 in LPMC). The present dataset is relevant for constraining models of mouse visual thalamocortical circuits, as well as for quantitative comparisons between genetically modified mouse strains, or across species.

S113 The thalamo-cortical system as central actor of NREM sleep

Neuronal activity in several brain regions is state dependent. This is best exemplified by the dramatic changes that occur in the electroencephalogram as states of vigilance transition from waking to sleep leading to brain waves of various frequencies. The main generator of these state dependent rhythmic activities is the thalamocortical system, a reciprocally interconnected network consisting of thalamocortical relay neurons, two types of thalamic inhibitory neurons including thalamic reticular neurons and local circuit interneurons and various neocortical principal cells and inhibitory interneurons. In the absence of sensory inputs, as happens during sleep and relaxed wakefulness neurons in the thalamus and neocortex engage in stereotyped rhythmic activity patterns spanning a wide range of frequencies, including slow waves, d-waves and sleep spindles. The generation of these rhythms is governed by an interplay between spatially and temporally coordinated synaptic interactions and intrinsic membrane properties of various thalamic and cortical neurons. Thalamic involvement in NREM sleep rhythms relies on a peculiar intrinsic cellular substrate of thalamic burst firing, the low-threshold Ca2+ spike. Cortico-thalamo-cortical synaptic interactions fine tune these intrinsic activity patterns to generate the plethora of state-dependent rhythmic activities.

Acetylcholine-dependent upregulation of TASK-1 channels in thalamic interneurons by a smooth muscle-like signalling pathway.

The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained K+ currents are modulated in thalamic neurons to control their activity modes; for the interneurons the molecular nature of the underlying ion channels is as yet unknown. Activation of TASK-1 K+ channels results in hyperpolarization of interneurons and suppression of their action potential firing. The modulation cascade involves a non-receptor tyrosine kinase, c-Src. The present study identifies a novel pathway for the activation of TASK-1 channels in CNS neurons that resembles cholinergic signalling and TASK-1 current modulation during hypoxia in smooth muscle cells. The dorsal part of the lateral geniculate nucleus (dLGN) is the main thalamic site for state-dependent transmission of visual information. Non-retinal inputs from the ascending arousal system and inhibition provided by γ-aminobutyric acid (GABA)ergic local circuit interneurons (INs) control neuronal activity within the dLGN. In particular, acetylcholine (ACh) depolarizes thalamocortical relay neurons by inhibiting two-pore domain potassium (K2P ) channels. Conversely, ACh also hyperpolarizes INs via an as-yet-unknown mechanism. By using whole cell patch-clamp recordings in brain slices and appropriate pharmacological tools we here report that stimulation of type 2 muscarinic ACh receptors induces IN hyperpolarization by recruiting the G-protein βγ subunit (Gβγ), class-1A phosphatidylinositol-4,5-bisphosphate 3-kinase, and cellular and sarcoma (c-Src) tyrosine kinase, leading to activation of two-pore domain weakly inwardly rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK)-1 channels. The latter was confirmed by the use of TASK-1-deficient mice. Furthermore inhibition of phospholipase Cβ as well as an increase in the intracellular level of phosphatidylinositol-3,4,5-trisphosphate facilitated the muscarinic effect. Our results have uncovered a previously unknown role of c-Src tyrosine kinase in regulating IN function in the brain and identified a novel mechanism by which TASK-1 channels are activated in neurons.

Tectal-derived interneurons contribute to phasic and tonic inhibition in the visual thalamus.

The release of GABA from local interneurons in the dorsal lateral geniculate nucleus (dLGN-INs) provides inhibitory control during visual processing within the thalamus. It is commonly assumed that this important class of interneurons originates from within the thalamic complex, but we now show that during early postnatal development Sox14/Otx2-expressing precursor cells migrate from the dorsal midbrain to generate dLGN-INs. The unexpected extra-diencephalic origin of dLGN-INs sets them apart from GABAergic neurons of the reticular thalamic nucleus. Using optogenetics we show that at increased firing rates tectal-derived dLGN-INs generate a powerful form of tonic inhibition that regulates the gain of thalamic relay neurons through recruitment of extrasynaptic high-affinity GABAA receptors. Therefore, by revising the conventional view of thalamic interneuron ontogeny we demonstrate how a previously unappreciated mesencephalic population controls thalamic relay neuron excitability.

Causal Role of Thalamic Interneurons in Brain State Transitions: A Study Using a Neural Mass Model Implementing Synaptic Kinetics.

Experimental studies on the Lateral Geniculate Nucleus (LGN) of mammals and rodents show that the inhibitory interneurons (IN) receive around 47.1% of their afferents from the retinal spiking neurons, and constitute around 20–25% of the LGN cell population. However, there is a definite gap in knowledge about the role and impact of IN on thalamocortical dynamics in both experimental and model-based research. We use a neural mass computational model of the LGN with three neural populations viz. IN, thalamocortical relay (TCR), thalamic reticular nucleus (TRN), to study the causality of IN on LGN oscillations and state-transitions. The synaptic information transmission in the model is implemented with kinetic modeling, facilitating the linking of low-level cellular attributes with high-level population dynamics. The model is parameterized and tuned to simulate alpha (8–13 Hz) rhythm that is dominant in both Local Field Potential (LFP) of LGN and electroencephalogram (EEG) of visual cortex in an awake resting state with eyes closed. The results show that: First, the response of the TRN is suppressed in the presence of IN in the circuit; disconnecting the IN from the circuit effects a dramatic change in the model output, displaying high amplitude synchronous oscillations within the alpha band in both TCR and TRN. These observations conform to experimental reports implicating the IN as the primary inhibitory modulator of LGN dynamics in a cognitive state, and that reduced cognition is achieved by suppressing the TRN response. Second, the model validates steady state visually evoked potential response in humans corresponding to periodic input stimuli; however, when the IN is disconnected from the circuit, the output power spectra do not reflect the input frequency. This agrees with experimental reports underpinning the role of IN in efficient retino-geniculate information transmission. Third, a smooth transition from alpha to theta band is observed by progressive decrease of neurotransmitter concentrations in the synaptic clefts; however, the transition is abrupt with removal of the IN circuitry in the model. The results imply a role of IN toward maintaining homeostasis in the LGN by suppressing any instability that may arise due to anomalous synaptic attributes.

Ascl1 and Helt act combinatorially to specify thalamic neuronal identity by repressing Dlxs activation

The mammalian thalamus is an essential diencephalic derivative that plays unique roles in processing and relaying sensory and motor information to and from the cerebral cortex. The profile of transcription factors and lineage tracing experiments revealed a spatiotemporal relationship between diencephalic progenitor domains and discrete differentiated neurons contributing to thalamic nuclei. However, the precise molecular mechanisms by which heterogeneous thalamic neurons become specified and assemble into distinct thalamic nuclei are still poorly understood. Here, we show that a combinatorial interaction between the bHLH transcription factors Ascl1 and Helt is required for acquiring thalamic progenitor identity. Surprisingly, in the combined absence of Ascl1 and Helt, rostral thalamic progenitors (TH-R) adopt a molecular profile of a more rostral diencephalic derivative, the prethalamus. Furthermore, we show that the prethalamic factors Dlxs upregulated by Ascl1/Helt deficiency play unique roles in regulating thalamic progenitor specification, and that derepression of Dlx2 and Dlx5 suppress generation of TH-R neurons. Taken together, our results suggest a model whereby the combined activity of two distinct bHLH factors plays a key role in the development of discrete classes of thalamic interneurons.

Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.

Studying the effects of thalamic interneurons in a thalamocortical neural mass model

Neural mass models of the thalamocortical circuitry are often used to mimic brain activity during sleep and wakefulness as observed in scalp electroencephalogram (EEG) signals [1]. It is understood that alpha rhythms (8-13 Hz) dominate the EEG power-spectra in the resting-state [2] as well as the period immediately before sleep [3]. Literature review shows that the thalamic interneurons (IN) are often ignored in thalamocortical population models; the emphasis is on the connections between the thalamo cortical relay (TCR) and the thalamic reticular nucleus (TRN). In this work, we look into the effects of the IN cell population on the behaviour of an existing thalamocortical model containing the TCR and TRN cell populations [4]. A schematic of the extended model used in this work is shown in Fig.1. The model equations are solved in Matlab using the Runge-Kutta method of the 4th/5th order. The model shows high sensitivity to the forward and reverse rates of reactions during synaptic transmission as well as on the membrane conductance of the cell populations. The input to the model is a white noise signal simulating conditions of resting state with eyes closed, a condition well known to be associated with dominant alpha band oscillations in EEG e.g. [5]. Thus, the model parameters are calibrated to obtain a set of basal parameter values when the model oscillates with a dominant frequency within the alpha band. The time series plots and the power spectra of the model output are compared with those when the IN cell population is disconnected from the circuit (by setting the inhibitory connectivity parameter from the IN to the TCR to zero). We observe (Fig. 2 inset) a significant difference in time series output of the TRN cell population with and without the IN cell population in the model; this in spite of the IN having no direct connectivity to and from the TRN cell population (Fig. 1). A comparison of the power spectra behaviour of the model output within the delta (1-3.5Hz), theta (3.75-7.5Hz), alpha (7.75-13.5Hz) and beta (13.75-30.5Hz) bands is shown in Fig. 2. Disconnecting the IN cell population shows a significant drop in the alpha band power and the dominant frequency of oscillation now lies within the theta band. An overall ‘slowing’ (left-side shift) of the power spectra is observed with an increase within the delta and theta bands and a decrease in the alpha and beta bands. Such a slowing of EEG is a signature of slow wave sleep in healthy individuals, and this suggests that the IN cell population may be centrally involved in the phase transition to slow wave sleep [6]. It is also characteristic of the waking EEG in Alzheimer’s disease, and may help us to understand the role of the IN cell population in modulating TCR and TRN cell behaviour in pathological brain conditions.

Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Local Dendrodendritic Inhibition Regulates Fast Synaptic Transmission in Visual Thalamus

Inhibition from thalamic interneurons plays a critical role in modulating information transfer between thalamus and neocortex. Interestingly, these neurons yield inhibition via two distinct outputs: presynaptic dendrites that innervate thalamocortical relay neurons and axonal outputs. Since the dendrites of thalamic interneurons are the primary targets of incoming synaptic information, it has been hypothesized that local synaptic input could produce highly focused dendritic output. To gain additional insight into the computational power of these presynaptic dendrites, we have combined two-photon laser scanning microscopy, glutamate uncaging, and whole-cell electrophysiological recordings to locally activate dendritic terminals and study their inhibitory contribution to rat thalamocortical relay neurons. Our findings demonstrate that local dendritic release from thalamic interneurons is controlled locally by AMPA/NMDA receptor-mediated recruitment of L-type calcium channels. Moreover, by mapping these connections with single dendrite resolution we not only found that presynaptic dendrites preferentially target proximal regions, but such actions differ significantly across branches. Furthermore, local stimulation of interneuron dendrites did not result in global excitation, supporting the notion that these interneurons can operate as multiplexors, containing numerous independently operating input-output devices.

Active Action Potential Propagation But Not Initiation in Thalamic Interneuron Dendrites

Inhibitory interneurons of the dorsal lateral geniculate nucleus of the thalamus modulate the activity of thalamocortical cells in response to excitatory input through the release of inhibitory neurotransmitter from both axons and dendrites. The exact mechanisms by which release can occur from dendrites are, however, not well understood. Recent experiments using calcium imaging have suggested that Na/K-based action potentials can evoke calcium transients in dendrites via local active conductances, making the backpropagating action potential a candidate for dendritic neurotransmitter release. In this study, we used high temporal and spatial resolution voltage-sensitive dye imaging to assess the characteristics of dendritic voltage deflections in response to Na/K action potentials in interneurons of the mouse dorsal lateral geniculate nucleus. We found that trains or single action potentials elicited by somatic current injection or local synaptic stimulation rapidly and actively backpropagated throughout the entire dendritic arbor and into the fine filiform dendritic appendages known to release GABAergic vesicles. Action potentials always appeared first in the soma or proximal dendrite in response to somatic current injection or local synaptic stimulation, and the rapid backpropagation into the dendritic arbor depended upon voltage-gated sodium and tetraethylammonium chloride-sensitive potassium channels. Our results indicate that thalamic interneuron dendrites integrate synaptic inputs that initiate action potentials, most likely in the axon initial segment, that then backpropagate with high fidelity into the dendrites, resulting in a nearly synchronous release of GABA from both axonal and dendritic compartments.

Rapid Plasticity of Visual Responses in the Adult Lateral Geniculate Nucleus

Compared to the developing visual system, where neuronal plasticity has been well characterized at multiple levels, little is known about plasticity in the adult, particularly within subcortical structures. We made intraocular injections of 2-amino-4-phosphonobutyric acid (APB) in adult cats to block visual responses in On-center retinal ganglion cells and examined the consequences on visual responses in the lateral geniculate nucleus (LGN) of the thalamus. In contrast to current views of retinogeniculate organization, which hold that On-center LGN neurons should become silent with APB, we find that ∼50% of On-center neurons rapidly develop Off-center responses. The time course of these emergent responses and the actions of APB in the retina indicate the plasticity occurs within the LGN. These results suggest there is greater divergence of retinogeniculate connections than previously recognized and that functionally silent, nonspecific retinal inputs can serve as a substrate for rapid plasticity in the adult.