Networks Of Excitatory Neurons Research Articles

Venom Peptides with Dual Modulatory Activity on the Voltage-Gated Sodium Channel NaV1.1 Provide Novel Leads for Development of Antiepileptic Drugs.

Voltage-gated sodium (NaV) channels play a fundamental role in normal neurological function, especially via the initiation and propagation of action potentials. The NaV1.1 subtype is found in inhibitory interneurons of the brain and it is essential for maintaining a balance between excitation and inhibition in neuronal networks. Heterozygous loss-of-function mutations of SCN1A, the gene encoding NaV1.1, underlie Dravet syndrome (DS), a severe pediatric epilepsy. We recently demonstrated that selective inhibition of NaV1.1 inactivation prevents seizures and premature death in a mouse model of DS. Thus, selective modulators of NaV1.1 might be useful therapeutics for treatment of DS as they target the underlying molecular deficit. Numerous scorpion-venom peptides have been shown to modulate the activity of NaV channels, but little is known about their activity at NaV1.1. Here we report the isolation, sequence, three-dimensional structure, recombinant production, and functional characterization of two peptidic modulators of NaV1.1 from venom of the buthid scorpion Hottentotta jayakari. These peptides, Hj1a and Hj2a, are potent agonists of NaV1.1 (EC50 of 17 and 32 nM, respectively), and they present dual α/β activity by modifying both the activation and inactivation properties of the channel. NMR studies of rHj1a indicate that it adopts a cystine-stabilized αβ fold similar to known scorpion toxins. Although Hj1a and Hj2a have only limited selectivity for NaV1.1, their unusual dual mode of action provides an alternative approach to the development of selective NaV1.1 modulators for the treatment of DS.

Generation of a knock-in MAP2-tdTomato reporter human embryonic stem cell line with inducible expression of NEUROG2/1 (NYGCe001-A).

Overexpression of NEUROG2 and NEUROG1 (NEUROG2/1) in human embryonic stem cells (hESCs) rapidly produces functional networks of excitatory and inhibitory neurons. To facilitate the use of this efficient inducible human neuron model in neuroscience research, we generated hESCs with doxycycline-inducible NEUROG2/1 via lentivirus and a tdTomato fluorescent reporter knock-in at the MAP2 locus using the CRISPR nuclease Cas9. Upon doxycycline-driven induction of NEUROG2/1, these hESCs differentiate within days into cells that are uniformly MAP2 immunoreactive and tdTomato fluorescent.

N-terminal alternative splicing of GluN1 regulates the maturation of excitatory synapses and seizure susceptibility

The majority of NMDA receptors (NMDARs) in the brain are composed of 2 GluN1 and 2 GluN2 subunits. The inclusion or exclusion of 1 N-terminal and 2 C-terminal domains of GluN1 results in 8 splicing variants that exhibit distinct temporal and spatial patterns of expression and functional properties. However, previous functional analyses of Grin1 variants have been done using heterologous expression and the in vivo function of Grin1 splicing is unknown. Here we show that N-terminal splicing of GluN1 has important functions in the maturation of excitatory synapses. The inclusion of exon 5 of Grin1 is up-regulated in several brain regions such as the thalamus and neocortex. We find that deletion of Grin1 exon 5 disrupts the developmental remodeling of NMDARs in thalamic neurons and the effect is distinct from that of Grin2a (GluN2A) deletion. Deletion of Grin2a or exon 5 of Grin1 alone partially attenuates the shortening of NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) during early life, whereas deletion of both Grin2a and exon 5 of Grin1 completely abolishes the developmental change in NMDAR-EPSC decay time. Deletion of exon 5 of Grin1 leads to an overproduction of excitatory synapses in layer 5 pyramidal neurons in the cortex and increases seizure susceptibility in adult mice. Our findings demonstrate that N-terminal splicing of GluN1 has important functions in synaptic maturation and neuronal network excitability.

Kainate receptors have different modulatory effect in seizure-like events and slow rhythmic activity in entorhinal cortex ex vivo

In the neocortex, neurons form functional networks, the members of which exhibit a variable degree of synchronization. Slow rhythmic activity may be regarded as a balanced interplay of excitatory and inhibitory neuronal network activity, which is essential in learning and memory consolidation. On the other hand, seizures may be considered as hypersynchronized network states occurring in epileptic diseases. The brain slice method and multi-electrode array (MEA) systems offer a good opportunity for the modelling of cortical spontaneous activities by examining their initiation and propagation. Our main goals were to characterise and compare spontaneous activities developing in different conditions and cortical network states. The role of kainate receptors in these processes was also tested. According to our results, there are demonstrable dissimilarities between slow rhythmic activities vs. seizure-like events developing in the rat entorhinal cortex ex vivo in normal vs. epileptic conditions. Propagation velocity, time scale, activity pattern and pharmacological sensitivity are all different. Kainate receptors play a role in network activity in entorhinal cortex, they are capable to prolong the duration of the events of epileptiform activity. Their regulatory effect is more prominent under epileptic than under normal conditions.

Cell type-specific gap junction network of excitatory neurons in the developing neocortex

Cell type-specific gap junction network of excitatory neurons in the developing neocortex

KCC2 antagonism increases neuronal network excitability but disrupts ictogenesis in vitro.

The potassium-chloride cotransporter 2 (KCC2) plays a role in epileptiform synchronization, but it remains unclear how it influences such a process. Here, we used tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced ictal and interictal activity. During 4AP application, ictal events were associated with significant increases in interneurons and principal cells activities. VU0463271 application transformed ictal discharges to shorter ictal-like events that were not accompanied by significant increases in interneuron or principal cell firing. Interictal events persisted during VU0463271 application at an accelerated frequency of occurrence with significant increases in interneuron and principal cell activity. Further analysis revealed that interneuron and principal cell firing rate during 4AP-induced interictal events were increased after VU0463271 application without changes in synchronicity. Overall, our results demonstrate that in the EC, KCC2 antagonism enhances both interneuron and principal cell excitability, while paradoxically decreasing the ability of neuronal networks to generate structured ictal events.NEW & NOTEWORTHY We are the first to use tetrode recordings in the entorhinal cortex to demonstrate that antagonizing potassium-chloride cotransporter 2 (KCC2) function abolishes ictal discharges and the associated, dynamic changes in single-unit firing in the in vitro 4-aminopyrine model of epileptiform synchronization. Interictal discharges were, however, shorter and more frequent during KCC2 antagonism, while the associated single-unit activity increased, suggesting augmented neuronal excitability. Our findings highlight the complex role of KCC2 in disease pathology.

Developmental Cell Death in the Cerebral Cortex.

In spite of the high metabolic cost of cellular production, the brain contains only a fraction of the neurons generated during embryonic development. In the rodent cerebral cortex, a first wave of programmed cell death surges at embryonic stages and affects primarily progenitor cells. A second, larger wave unfolds during early postnatal development and ultimately determines the final number of cortical neurons. Programmed cell death in the developing cortex is particularly dependent on neuronal activity and unfolds in a cell-specific manner with precise temporal control. Pyramidal cells and interneurons adjust their numbers in sync, which is likely crucial for the establishment of balanced networks of excitatory and inhibitory neurons. In contrast, several other neuronal populations are almost completely eliminated through apoptosis during the first two weeks of postnatal development, highlighting the importance of programmed cell death in sculpting the mature cerebral cortex.

Robust Associative Learning Is Sufficient to Explain the Structural and Dynamical Properties of Local Cortical Circuits.

The ability of neural networks to associate successive states of network activity lies at the basis of many cognitive functions. Hence, we hypothesized that many ubiquitous structural and dynamical properties of local cortical networks result from associative learning. To test this hypothesis, we trained recurrent networks of excitatory and inhibitory neurons on memories composed of varying numbers of associations and compared the resulting network properties with those observed experimentally. We show that, when the network is robustly loaded with near-maximum amount of associations it can support, it develops properties that are consistent with the observed probabilities of excitatory and inhibitory connections, shapes of connection weight distributions, overexpression of specific 2- and 3-neuron motifs, distributions of connection numbers in clusters of 3-8 neurons, sustained, irregular, and asynchronous firing activity, and balance of excitation and inhibition. In addition, memories loaded into the network can be retrieved, even in the presence of noise that is comparable with the baseline variations in the postsynaptic potential. The confluence of these results suggests that many structural and dynamical properties of local cortical networks are simply a byproduct of associative learning. We predict that overexpression of excitatory-excitatory bidirectional connections observed in many cortical systems must be accompanied with underexpression of bidirectionally connected inhibitory-excitatory neuron pairs.SIGNIFICANCE STATEMENT Many structural and dynamical properties of local cortical networks are ubiquitously present across areas and species. Because synaptic connectivity is shaped by experience, we wondered whether continual learning, rather than genetic control, is responsible for producing such features. To answer this question, we developed a biologically constrained recurrent network of excitatory and inhibitory neurons capable of learning predefined sequences of network states. Embedding such associative memories into the network revealed that, when individual neurons are robustly loaded with a near-maximum amount of memories they can support, the network develops many properties that are consistent with experimental observations. Our findings suggest that basic structural and dynamical properties of local networks in the brain are simply a byproduct of learning and memory storage.

Neurons Derived from Human Induced Pluripotent Stem Cells Integrate into Rat Brain Circuits and Maintain Both Excitatory and Inhibitory Synaptic Activities

The human cerebral cortex is a complex structure with tightly interconnected excitatory and inhibitory neuronal networks. In order to study human cortical function, we recently developed a method to generate cortical neurons from human induced pluripotent stem cells (hiPSCs) that form both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. These cultures and organoids recapitulate neuronal populations representative of the six cortical layers and a balanced excitatory and inhibitory network that is functional and homeostatically stable. To determine whether hiPSC-derived neurons can integrate and retain physiologic activities in vivo, we labeled hiPSCs with red fluorescent protein (RFP) and introduced hiPSC-derived neural progenitors to rat brains. Efficient neural induction, followed by differentiation resulted in a RFP+ neural population with traits of forebrain identity and a balanced synaptic activity composed of both excitatory neurons and inhibitory interneurons. Ten weeks after transplantation, grafted cells structurally integrated into the rat forebrain. Remarkably, these hiPSC-derived neurons were able to fire, exhibiting both excitatory and inhibitory postsynaptic currents, which culminates in the establishment of neuronal connectivity with the host circuitry. This study demonstrates that neural progenitors derived from hiPSCs can differentiate into functional cortical neurons and can participate in neural network activity through functional synaptic integration in vivo, thereby contributing to information processing.

A Subfornical Organ→Paraventricular Nucleus Neuronal Network Contributes to Non‐Alcoholic Fatty Liver Disease via Hepatic Sympathetic Outflow

Non‐alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, affects 1 in 3 adults and leads to an increased risk for metabolic and cardiovascular diseases. Our recent work indicates that obesity‐induced NAFLD is mediated by elevations in hepatic sympathetic nerve activity. However, the neural pathways that contribute to hepatic sympathetic overactivity and subsequent NAFLD development remain unknown. The subfornical organ (SFO) ‐ a forebrain circumventricular region that lies outside the blood brain barrier ‐ senses, integrates and responds to circulating stimuli. Anatomical and electrophysiological data support dense, excitatory projections from the SFO to the paraventricular nucleus of the hypothalamus (SFO→PVN), an integrative nucleus with direct hepatic spinal projections. Taken together, we hypothesized that an SFO→PVN excitatory neuronal network causes hepatic steatosis via elevations in liver sympathetic outflow. An intersectional viral strategy was used in which a retrograde transported canine adenovirus was targeted to the PVN to express Cre‐recombinase in SFO→PVN neurons (CAV2‐Cre‐GFP). This was combined with SFO‐targeted delivery of a Cre‐inducible designer receptors engineered against designer drugs (DREADDs) excitatory construct (AAV2‐DIO‐hM3Gq‐mCherry). With this approach, the pharmacological ligand clozapine‐N‐oxide (CNO; 3 mg/kg i.p.) was administered once daily over 6 days to activate SFO→PVN neurons (n=4). Short‐term activation of SFO→PVN neurons resulted in hepatic steatosis (2.6±0.02 vs 2.9±0.02 density*107, saline vs CNO, p<0.05) that was paralleled by an elevation in liver tyrosine hydroxylase protein (1.8±0.4 CNO fold saline, p<0.05), the rate‐limiting enzyme for catecholamine synthesis within postganglionic nerve terminals. Based on this, we combined the above viral strategy with selective hepatic denervation (phenol application) or sham surgery (n=5–6). Oil Red O staining (Figure 1) demonstrated that hepatic denervation prevented liver lipid accumulation in response to 6‐day activation of SFO→PVN neurons (1.9±0.01 vs 1.7±0.01 density*107, CNO sham vs CNO denervation, p<0.05). Importantly, this occurred independent of changes in body weight and food intake. Hepatic denervation was confirmed by a reduction in liver tyrosine hydroxlase protein expression (0.3±0.1 vs 1.8±0.3 vs 0.4±0.1 fold saline sham, CNO sham vs saline denervation vs CNO denervation, all p<0.05). Lastly, male C57Bl/6 mice that were fed a high fat diet (10 wks) underwent intersectional viral targeting for expression of an inhibitory DREADDs construct (AAV2‐DIO‐hM4Gi‐mCherry) in SFO→PVN neurons. Remarkably, acute inhibition of SFO→PVN neurons in obese mice resulted in an approximate 45% reduction in hepatic steatosis (Figure 2, n=4/group). Collectively, these findings indicate that activation of SFO→PVN neurons causes liver triglyceride deposition via elevations in hepatic sympathetic outflow. Furthermore, in the context of obesity, inhibition of this forebrain‐hypothalamic‐autonomic circuit results in a marked reduction in NAFLD.Support or Funding InformationR01DK117007This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Alterations in GABAA-Receptor Trafficking and Synaptic Dysfunction in Brain Disorders.

GABAA receptors (GABAAR) are the major players in fast inhibitory neurotransmission in the central nervous system (CNS). Regulation of GABAAR trafficking and the control of their surface expression play important roles in the modulation of the strength of synaptic inhibition. Different pieces of evidence show that alterations in the surface distribution of GABAAR and dysregulation of their turnover impair the activity of inhibitory synapses. A diminished efficacy of inhibitory neurotransmission affects the excitatory/inhibitory balance and is a common feature of various disorders of the CNS characterized by an increased excitability of neuronal networks. The synaptic pool of GABAAR is mainly controlled through regulation of internalization, recycling and lateral diffusion of the receptors. Under physiological condition these mechanisms are finely coordinated to define the strength of GABAergic synapses. In this review article, we focus on the alteration in GABAAR trafficking with an impact on the function of inhibitory synapses in various disorders of the CNS. In particular we discuss how similar molecular mechanisms affecting the synaptic distribution of GABAAR and consequently the excitatory/inhibitory balance may be associated with a wide diversity of pathologies of the CNS, from psychiatric disorders to acute alterations leading to neuronal death. A better understanding of the cellular and molecular mechanisms that contribute to the impairment of GABAergic neurotransmission in these disorders, in particular the alterations in GABAAR trafficking and surface distribution, may lead to the identification of new pharmacological targets and to the development of novel therapeutic strategies.

Alzheimer Aβ Assemblies Accumulate in Excitatory Neurons upon Proteasome Inhibition and Kill Nearby NAKα3 Neurons by Secretion

SummaryWe identified ∼30-mer amyloid-β protein (Aβ) assemblies, termed amylospheroids, from brains of patients with Alzheimer disease (AD) as toxic entities responsible for neurodegeneration and showed that Na+,K+-ATPase α3 (NAKα3) is the sole target of amylospheroid-mediated neurodegeneration. However, it remains unclear where in neurons amylospheroids form and how they reach their targets to induce neurodegeneration. Here, we present an in vitro culture system designed to chronologically follow amylospheroid formation in mature neurons expressing amyloid precursor protein bearing early-onset AD mutations. Amylospheroids were found to accumulate mainly in the trans-Golgi network of excitatory neurons and were initially transported in axons. Proteasome inhibition dramatically increased amylospheroid amounts in trans-Golgi by increasing Aβ levels and induced dendritic transport. Amylospheroids were secreted and caused the degeneration of adjacent NAKα3-expressing neurons. Interestingly, the ASPD-producing neurons later died non-apoptotically. Our findings demonstrate a link between ASPD levels and proteasome function, which may have important implications for AD pathophysiology.

Overexpression of NEUROG2 and NEUROG1 in human embryonic stem cells produces a network of excitatory and inhibitory neurons.

Overexpression of mouse neurogenin ( Neurog) 2 alone or in combination with mouse Neurog2/1 in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) can rapidly produce high-yield excitatory neurons. Here, we report a detailed characterization of human neuronal networks induced by the expression of human NEUROG2 together with human NEUROG2/1 in hESCs using molecular, cellular, and electrophysiological measurements over 60 d after induction. Both excitatory synaptic transmission and network firing activity increased over time. Strikingly, inhibitory synaptic transmission and GABAergic cells were identified from NEUROG2/1 induced neurons (iNs). To illustrate the application of such iNs, we demonstrated that the heterozygous knock out of SCN2A, whose loss-of-function mutation is strongly implicated in autism risk, led to a dramatic reduction in network activity in the NEUROG2/1 iNs. Our findings not only extend our understanding of the NEUROG2/1-induced human neuronal network but also substantiate NEUROG2/1 iNs as an in vitro system for modeling neuronal and functional deficits on a human genetic background.-Lu, C., Shi, X., Allen, A., Baez-Nieto, D., Nikish, A., Sanjana, N. E., Pan, J. Q. Overexpression of NEUROG2 and NEUROG1 in human embryonic stem cells produces a network of excitatory and inhibitory neurons.

Oscillatory Rhythms in a Model Network of Excitatory and Inhibitory Neurons

Oscillatory rhythms are investigated in a model network where a pair of excitatory neurons interact via an inhibitory neuron. Each individual neuron is modeled as a relaxation oscillator, and a slow/fast decomposition process reduces the problem of a stable oscillatory rhythm to the problem of a stable fixed point of a map. Further reduction of the map is made by finding an invariant manifold. A detailed analysis of the reduced map reveals how different types of stable oscillatory rhythms arise, depending on the intrinsic properties of the individual neurons and the synaptic time constant.

Network remodeling induced by transcranial brain stimulation: A computational model of tDCS-triggered cell assembly formation.

Transcranial direct current stimulation (tDCS) is a variant of noninvasive neuromodulation, which promises treatment for brain diseases like major depressive disorder. In experiments, long-lasting aftereffects were observed, suggesting that persistent plastic changes are induced. The mechanism underlying the emergence of lasting aftereffects, however, remains elusive. Here we propose a model, which assumes that tDCS triggers a homeostatic response of the network involving growth and decay of synapses. The cortical tissue exposed to tDCS is conceived as a recurrent network of excitatory and inhibitory neurons, with synapses subject to homeostatically regulated structural plasticity. We systematically tested various aspects of stimulation, including electrode size and montage, as well as stimulation intensity and duration. Our results suggest that transcranial stimulation perturbs the homeostatic equilibrium and leads to a pronounced growth response of the network. The stimulated population eventually eliminates excitatory synapses with the unstimulated population, and new synapses among stimulated neurons are grown to form a cell assembly. Strong focal stimulation tends to enhance the connectivity within new cell assemblies, and repetitive stimulation with well-chosen duty cycles can increase the impact of stimulation even further. One long-term goal of our work is to help in optimizing the use of tDCS in clinical applications.

Impact of Hyperventilation and Sleep Deprivation Upon Visual Evoked Potentials in Patients with Epilepsy.

The diagnosis of epilepsy can cause many problems, especially when the routine electrophysiological tests are inconclusive. The aim of the present study was to assess the visual evoked potential (VEP) in patients with epilepsy using various kinds of stimulation and activation tests. The VEP parameters were also presented with reference to the type of seizure and abnormalities in electroencephalogram (EEG), including the response to the activation tests. This study comprised 81 patients with newly diagnosed epilepsy of unknown etiology before initiation of the treatment. The VEP tests were performed at rest, after hyperventilation, and deprivation of sleep. Visual stimulation included an alternating checkerboard pattern and a uniform flash light (FL) with a frequency of 1.88 and 15 Hz. The VEP parameters obtained with the stimulation of a checkerboard pattern did not differ significantly between the patients and controls. Neither the presence of seizure activity in EEG nor the type of seizure significantly affected the VEP parameters. Using the FL stimulation, a significantly prolonged VEP latency was found at the FL frequency of 1.88 Hz and shortened at the frequency of 15 Hz. These changes were augmented after activation tests. In case of the patients with positive intermittent photic stimulation response in EEG, a significant prolongation of P100 latency was shown at rest and after FL stimulation at the frequency of 1.88 Hz. Standard activation methods significantly affect the VEP parameters in patients with epilepsy. Changes in the VEP parameters depend on the frequency and the type of the stimulus, as well as the activation method used. These findings suggest a disturbed balance between the glutamatergic and GABAergic systems in the visual excitability of neuronal networks in case of patients with epilepsy.

Ih contributes to increased motoneuron excitability in restless legs syndrome.

Restless legs patients complain about sensory and motor symptoms leading to sleep disturbances. Symptoms include painful sensations, an urge to move and involuntary leg movements. The responsible mechanisms of restless legs syndrome are still not known, although current studies indicate an increased neuronal network excitability. Reflex studies indicate the involvement of spinal structures. Peripheral mechanisms have not been investigated so far. In the present study, we provide evidence of increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated inward rectification in motor axons. The excitability of sensory axons was not changed. We conclude that, in restless legs syndrome, an increased HCN current in motoneurons may play a pathophysiological role, such that these channels could represent a valuable target for pharmaceutical intervention. Restless legs syndrome is a sensorimotor network disorder. So far, the responsible pathophysiological mechanisms are poorly understood. In the present study, we provide evidence that the excitability of peripheral motoneurons contributes to the pathophysiology of restless legs syndrome. In vivo excitability studies on motor and sensory axons of the median nerve were performed on patients with idiopathic restless legs syndrome (iRLS) who were not currently on treatment. The iRLS patients had greater accommodation in motor but not sensory axons to long-lasting hyperpolarization compared to age-matched healthy subjects, indicating greater inward rectification in iRLS. The most reasonable explanation is that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open at less hyperpolarized membrane potentials, a view supported by mathematical modelling. The half-activation potential for HCN channels (Bq) was the single best parameter that accounted for the difference between normal controls and iRLS data. A 6mV depolarization of Bq reduced the discrepancy between the normal control model and the iRLS data by 92.1%. Taken together, our results suggest an increase in the excitability of motor units in iRLS that could enhance the likelihood of leg movements. The abnormal axonal properties are consistent with other findings indicating that the peripheral system is part of the network involved in iRLS.

Assembly and Trafficking of Homomeric and Heteromeric Kainate Receptors with Impaired Ligand Binding Sites

Kainate receptors (KARs) are a subfamily of ionotropic glutamate receptors (iGluRs) mediating excitatory synaptic transmission. Cell surface expressed KARs modulate the excitability of neuronal networks. The transfer of iGluRs from the endoplasmic reticulum (ER) to the cell surface requires occupation of the agonist binding sites. Here we used molecular modelling to produce a range of ligand binding domain (LBD) point mutants of GluK1–3 KAR subunits with and without altered agonist efficacy to further investigate the role of glutamate binding in surface trafficking and activation of homomeric and heteromeric KARs using endoglycosidase digestion, cell surface biotinylation and imaging of changes in intracellular Ca2+ concentration [Ca2+]i. Mutations of conserved amino acid residues in the LBD that disrupt agonist binding to GluK1–3 (GluK1-T675V, GluK2-A487L, GluK2-T659V and GluK3-T661V) reduced both the total expression levels and cell surface delivery of all of these mutant subunits compared to the corresponding wild type in transiently transfected human embryonic kidney 293 (HEK293) cells. In contrast, the exchange of non-conserved residues in the LBD that convert antagonist selectivity of GluK1–3 (GluK1-T503A, GluK2-A487T, GluK3-T489A, GluK1-N705S/S706N, GluK2-S689N/N690S, GluK3-N691S) did not alter the biosynthesis and trafficking of subunit proteins. Co-assembly of mutant GluK2 with an impaired LBD and wild type GluK5 subunits enables the cell surface expression of both subunits. However, [Ca2+]i imaging indicates that the occupancy of both GluK2 and GluK5 LBDs is required for the full activation of GluK2/GluK5 heteromeric KAR channels.

Learning recurrent dynamics in spiking networks.

Spiking activity of neurons engaged in learning and performing a task show complex spatiotemporal dynamics. While the output of recurrent network models can learn to perform various tasks, the possible range of recurrent dynamics that emerge after learning remains unknown. Here we show that modifying the recurrent connectivity with a recursive least squares algorithm provides sufficient flexibility for synaptic and spiking rate dynamics of spiking networks to produce a wide range of spatiotemporal activity. We apply the training method to learn arbitrary firing patterns, stabilize irregular spiking activity in a network of excitatory and inhibitory neurons respecting Dale's law, and reproduce the heterogeneous spiking rate patterns of cortical neurons engaged in motor planning and movement. We identify sufficient conditions for successful learning, characterize two types of learning errors, and assess the network capacity. Our findings show that synaptically-coupled recurrent spiking networks possess a vast computational capability that can support the diverse activity patterns in the brain.

Network mechanisms underlying the role of oscillations in cognitive tasks.

Oscillatory activity robustly correlates with task demands during many cognitive tasks. However, not only are the network mechanisms underlying the generation of these rhythms poorly understood, but it is also still unknown to what extent they may play a functional role, as opposed to being a mere epiphenomenon. Here we study the mechanisms underlying the influence of oscillatory drive on network dynamics related to cognitive processing in simple working memory (WM), and memory recall tasks. Specifically, we investigate how the frequency of oscillatory input interacts with the intrinsic dynamics in networks of recurrently coupled spiking neurons to cause changes of state: the neuronal correlates of the corresponding cognitive process. We find that slow oscillations, in the delta and theta band, are effective in activating network states associated with memory recall. On the other hand, faster oscillations, in the beta range, can serve to clear memory states by resonantly driving transient bouts of spike synchrony which destabilize the activity. We leverage a recently derived set of exact mean-field equations for networks of quadratic integrate-and-fire neurons to systematically study the bifurcation structure in the periodically forced spiking network. Interestingly, we find that the oscillatory signals which are most effective in allowing flexible switching between network states are not smooth, pure sinusoids, but rather burst-like, with a sharp onset. We show that such periodic bursts themselves readily arise spontaneously in networks of excitatory and inhibitory neurons, and that the burst frequency can be tuned via changes in tonic drive. Finally, we show that oscillations in the gamma range can actually stabilize WM states which otherwise would not persist.