Dendritic Excitability Research Articles

Local changes in potassium ions regulate input integration in active dendrites.

During neuronal activity, the extracellular concentration of potassium ions ([K+]o) increases substantially above resting levels, yet it remains unclear what role these [K+]o changes play in the dendritic integration of synaptic inputs. We here used mathematical formulations and biophysical modeling to explore the role of synaptic activity-dependent K+ changes in dendritic segments of a visual cortex pyramidal neuron, receiving inputs tuned to stimulus orientation. We found that the spatial arrangement of inputs dictates the magnitude of [K+]o changes in the dendrites: Dendritic segments receiving similarly tuned inputs can attain substantially higher [K+]o increases than segments receiving diversely tuned inputs. These [K+]o elevations in turn increase dendritic excitability, leading to more robust and prolonged dendritic spikes. Ultimately, these local effects amplify the gain of neuronal input-output transformations, causing higher orientation-tuned somatic firing rates without compromising orientation selectivity. Our results suggest that local, activity-dependent [K+]o changes in dendrites may act as a "volume knob" that determines the impact of synaptic inputs on feature-tuned neuronal firing.

Synapse-to-nucleus ERK-CREB transcriptional signaling requires dendrite-to-soma Ca2+propagation mediated by L-type voltage-gated Ca2+ channels.

The cAMP-response element binding protein (CREB) transcription factor controls the expression of the neuronal immediate early genes c-Fos, Arc, and Bdnf and is essential for long-lasting synaptic plasticity underlying learning and memory. Despite this critical role, there is still ongoing debate regarding the synaptic excitation-transcription (E-T) coupling mechanisms mediating CREB activation in the nucleus. Here we employed optical uncaging of glutamate to mimic synaptic excitation of distal dendrites in conjunction with simultaneous imaging of intracellular Ca2+ dynamics and transcriptional reporter gene expression to elucidate CREB E-T coupling mechanisms in hippocampal neurons cultured from both male and female rats. Using this approach, we found that CREB-dependent transcription was engaged following dendritic stimulation of N-methyl, D-aspartate receptors (NMDARs) only when Ca2+ signals propagated to the soma via subsequent activation of L-type voltage-gated Ca2+ channels resulting in activation of Extracellular signal-Regulated Kinase (ERK) MAP kinase signaling to sustain CREB phosphorylation in the nucleus. In contrast, dendrite-restricted Ca2+ signals generated by NMDARs failed to stimulate CREB-dependent transcription. Furthermore, Ca2+-CaM-dependent kinase (CaMK)-mediated signaling pathways that may transiently contribute to CREB-phosphorylation following stimulation were ultimately dispensable for downstream CREB-dependent transcription and c-Fos induction. These findings emphasize the essential role that L-type Ca2+ channels play in rapidly relaying signals over long distances from synapses located on distal dendrites to the nucleus to control gene expression.Significance Statement The transcription factor CREB controls gene expression programs required for long-lasting synaptic plasticity and learning and memory, yet the synapse-to-nucleus signaling mechanisms mediating CREB activation are still unclear. Using glutamate uncaging to mimic synaptic input to dendrites, this study shows that Ca2+ signals propagated to the soma by L-type voltage-gated Ca2+ channels engage the ERK MAP kinase cascade to mediate CREB phosphorylation and CREB-dependent transcription. In contrast, dendrite-restricted Ca2+ signals generated primarily by NMDARs failed to effectively engage this signaling pathway or CREB-dependent transcription. In addition, we found that while ERK and CaMK pathways may both contribute to increased CREB phosphorylation immediately following neuronal stimulation, sustained ERK signaling to CREB was necessary to effectively drive CREB-dependent transcription.

Differences in the consolidation by spontaneous and evoked ripples in the presence of active dendrites.

Ripples are a typical form of neural activity in hippocampal neural networks associated with the replay of episodic memories during sleep as well as sleep-related plasticity and memory consolidation. The emergence of ripples has been observed both dependent as well as independent of input from other brain areas and often coincides with dendritic spikes. Yet, it is unclear how input-evoked and spontaneous ripples as well as dendritic excitability affect plasticity and consolidation. Here, we use mathematical modeling to compare these cases. We find that consolidation as well as the emergence of spontaneous ripples depends on a reliable propagation of activity in feed-forward structures which constitute memory representations. This propagation is facilitated by excitable dendrites, which entail that a few strong synapses are sufficient to trigger neuronal firing. In this situation, stimulation-evoked ripples lead to the potentiation of weak synapses within the feed-forward structure and, thus, to a consolidation of a more general sequence memory. However, spontaneous ripples that occur without stimulation, only consolidate a sparse backbone of the existing strong feed-forward structure. Based on this, we test a recently hypothesized scenario in which the excitability of dendrites is transiently enhanced after learning, and show that such a transient increase can strengthen, restructure and consolidate even weak hippocampal memories, which would be forgotten otherwise. Hence, a transient increase in dendritic excitability would indeed provide a mechanism for stabilizing memories.

Optogenetic Interrogation of Electrophysiological Dendritic Properties and Their Effect on Pacemaking Neurons from Acute Rodent Brain Slices.

Understanding dendritic excitability is essential for a complete and precise characterization of neurons' input-output relationships. Theoretical and experimental work demonstrates that the electrotonic and nonlinear properties of dendrites can alter the amplitude (e.g., through amplification) and latency of synaptic inputs as viewed in the axosomatic region where spike timing is determined. The gold-standard technique to study dendritic excitability is using dual-patch recordings with a high-resistance electrode used to patch a piece of distal dendrite in addition to a somatic patch electrode. However, this approach is often impractical when distal dendrites are too fine to patch. Therefore, we developed a technique that utilizes the expression of Channelrhodopsin-2 (ChR2) to study dendritic excitability in acute brain slices through the combination of a somatic patch electrode and optogenetic activation. The protocol describes how to prepare acute slices from mice that express ChR2 in specific cell types, and how to use two modes of light stimulation: proximal (which activates the soma and proximal dendrites in a ~100 µm diameter surrounding the soma) with the use of a high-magnification objective and full-field stimulation through a low-magnification objective (which activates the entire somato-dendritic field of the neuron). We use this technique in conjunction with various stimulation protocols to estimate model-based spectral components of dendritic filtering and the impact of dendrites on phase response curves, peri-stimulus time histograms, and entrainment of pacemaking neurons. This technique provides a novel use of optogenetics to study intrinsic dendritic excitability through the use of standard patch-clamp slice physiology. Key features • A method for studying the effects of electrotonic and nonlinear dendritic properties on the sub- and suprathreshold responses of pacemaking neurons. • Combines somatic patch clamp or perforated patch recordings with optogenetic activation in acute brain slices to investigate dendritic linear transformation without patching the dendrite. • Oscillatory illumination at various frequencies estimates spectral properties of the dendrite using subthreshold voltage-clamp recordings and studies entrainment of pacemakers in current clamp recordings. • This protocol uses Poisson white noise illumination to estimate dendritic phase response curves and peri-stimulus time histograms.

Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel NaV1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how NaV1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.

Dendritic excitability controls overdispersion.

The brain is an intricate assembly of intercommunicating neurons whose input-output function is only partially understood. The role of active dendrites in shaping spiking responses, in particular, is unclear. Although existing models account for active dendrites and spiking responses, they are too complex to analyze analytically and demand long stochastic simulations. Here we combine cable and renewal theory to describe how input fluctuations shape the response of neuronal ensembles with active dendrites. We found that dendritic input readily and potently controls interspike interval dispersion. This phenomenon can be understood by considering that neurons display three fundamental operating regimes: one mean-driven regime and two fluctuation-driven regimes. We show that these results are expected to appear for a wide range of dendritic properties and verify predictions of the model in experimental data. These findings have implications for the role of interspike interval dispersion in learning and for theories of attractor states.

Trophoblast glycoprotein is required for efficient synaptic vesicle exocytosis from retinal rod bipolar cells.

Rod bipolar cells (RBCs) faithfully transmit light-driven signals from rod photoreceptors in the outer retina to third order neurons in the inner retina. Recently, significant work has focused on the role of leucine-rich repeat (LRR) proteins in synaptic development and signal transduction at RBC synapses. We previously identified trophoblast glycoprotein (TPBG) as a novel transmembrane LRR protein localized to the dendrites and axon terminals of RBCs. We examined the effects on RBC physiology and retinal processing of TPBG genetic knockout in mice using immunofluorescence and electron microscopy, electroretinogram recording, patch-clamp electrophysiology, and time-resolved membrane capacitance measurements. The scotopic electroretinogram showed a modest increase in the b-wave and a marked attenuation in oscillatory potentials in the TPBG knockout. No effect of TPBG knockout was observed on the RBC dendritic morphology, TRPM1 currents, or RBC excitability. Because scotopic oscillatory potentials primarily reflect RBC-driven rhythmic activity of the inner retina, we investigated the contribution of TPBG to downstream transmission from RBCs to third-order neurons. Using electron microscopy, we found shorter synaptic ribbons in TPBG knockout axon terminals in RBCs. Time-resolved capacitance measurements indicated that TPBG knockout reduces synaptic vesicle exocytosis and subsequent GABAergic reciprocal feedback without altering voltage-gated Ca2+ currents. TPBG is required for normal synaptic ribbon development and efficient neurotransmitter release from RBCs to downstream cells. Our results highlight a novel synaptic role for TPBG at RBC ribbon synapses and support further examination into the mechanisms by which TPBG regulates RBC physiology and circuit function.

Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior

Deletion of the obsessive-compulsive disorder (OCD)-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at corticostriatal synapses, causes OCD-like motor behaviors in mice. While corticostriatal synaptic dysfunction is central to this phenotype, the striatum efficiently adapts to pathological changes, often in ways that expand upon the original circuit impairment. Here, we show that SAPAP3 deletion causes non-synaptic and pathway-specific alterations in dorsolateral striatum circuit function. While somatic excitability was elevated in striatal projection neurons (SPNs), dendritic excitability was exclusively enhanced in direct pathway SPNs. Layered on top of this, cholinergic modulation was altered in opposing ways: striatal cholinergic interneuron density and evoked acetylcholine release were elevated, while basal muscarinic modulation of SPNs was reduced. These data describe how SAPAP3 deletion alters the striatal landscape upon which impaired corticostriatal inputs will act, offering a basis for how pathological synaptic integration and unbalanced striatal output underlying OCD-like behaviors may be shaped.

A Pathogenic Missense Mutation in Kainate Receptors Elevates Dendritic Excitability and Synaptic Integration through Dysregulation of SK Channels.

Numerous rare variants that cause neurodevelopmental disorders (NDDs) occur within genes encoding synaptic proteins, including ionotropic glutamate receptors. However, in many cases, it remains unclear how damaging missense variants affect brain function. We determined the physiological consequences of an NDD causing missense mutation in the GRIK2 kainate receptor (KAR) gene, that results in a single amino acid change p.Ala657Thr in the GluK2 receptor subunit. We engineered this mutation in the mouse Grik2 gene, yielding a GluK2(A657T) mouse, and studied mice of both sexes to determine how hippocampal neuronal function is disrupted. Synaptic KAR currents in hippocampal CA3 pyramidal neurons from heterozygous A657T mice exhibited slow decay kinetics, consistent with incorporation of the mutant subunit into functional receptors. Unexpectedly, CA3 neurons demonstrated elevated action potential spiking because of downregulation of the small-conductance Ca2+ activated K+ channel (SK), which mediates the post-spike afterhyperpolarization. The reduction in SK activity resulted in increased CA3 dendritic excitability, increased EPSP-spike coupling, and lowered the threshold for the induction of LTP of the associational-commissural synapses in CA3 neurons. Pharmacological inhibition of SK channels in WT mice increased dendritic excitability and EPSP-spike coupling, mimicking the phenotype in A657T mice and suggesting a causative role for attenuated SK activity in aberrant excitability observed in the mutant mice. These findings demonstrate that a disease-associated missense mutation in GRIK2 leads to altered signaling through neuronal KARs, pleiotropic effects on neuronal and dendritic excitability, and implicate these processes in neuropathology in patients with genetic NDDs.SIGNIFICANCE STATEMENT Damaging mutations in genes encoding synaptic proteins have been identified in various neurodevelopmental disorders, but the functional consequences at the cellular and circuit level remain elusive. By generating a novel knock-in mutant mouse, this study examined the role of a pathogenic mutation in the GluK2 kainate receptor (KAR) subunit, a subclass of ionotropic glutamate receptors. Analyses of hippocampal CA3 pyramidal neurons determined elevated action potential firing because of an increase in dendritic excitability. Increased dendritic excitability was attributable to reduced activity of a Ca2+ activated K+ channel. These results indicate that a pathogenic KAR mutation results in dysregulation of dendritic K+ channels, which leads to an increase in synaptic integration and backpropagation of action potentials into distal dendrites.

LHPP in Glutamatergic Neurons of the Ventral Hippocampus Mediates Depression-like Behavior by Dephosphorylating CaMKIIα and ERK

BackgroundLHPP was recently shown to be a risk gene for major depressive disorder. LHPP has been proven to dephosphorylate the residues of histidine, serine, threonine, and tyrosine. However, much remains unknown about how LHPP contributes to depression. MethodsIn the current study, we addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing, and electrophysiology. ResultsWe found that levels of LHPP were upregulated in glutamatergic neurons of the ventral hippocampus in mice that displayed stress-induced depression-like behaviors. Knockout of LHPP in glutamatergic neurons of the brain improved the spontaneous activity of LHPPflox/flox·CaMKIIαCre+ (conditional knockout) mice. Adeno-associated virus–mediated LHPP knockdown in the ventral hippocampus enhanced resistance against chronic social defeat stress in mice. Manipulations of LHPP levels impacted the density of dendritic spines and excitability of CA1 pyramidal neurons by mediating the expressions of BDNF (brain-derived neurotrophic factor) and PSD95 via the modulation of the dephosphorylation of CaMKIIα and ERK. Notably, compared with wild-type LHPP, human mutant LHPP (E56K, S57L) significantly increased the activity of the CaMKIIα/ERK-BDNF/PSD95 signaling pathway. Finally, esketamine, not fluoxetine, markedly alleviated the LHPP upregulation–induced depression-like behaviors. ConclusionsThese findings provide evidence that LHPP contributes to the pathogenesis of depression via threonine and serine hydrolases, thereby identifying LHPP as a potential therapeutic target in treating patients with major depressive disorder.

A dietary polyphenol metabolite alters CA1 excitability ex vivo and mildly affects cortico-hippocampal field potential generators in anesthetized animals.

Dietary polyphenols have beneficial effects in situations of impaired cognition in acute models of neurodegeneration. The possibility that they may have a direct effect on the electrical activity of neuronal populations has not been tested. We explored the electrophysiological action of protocatechuic acid (PCA) on CA1 pyramidal cells ex vivo and network activity in anesthetized female rats using pathway-specific field potential (FP) generators obtained from laminar FPs in cortex and hippocampus. Whole-cell recordings from CA1 pyramidal cells revealed increased synaptic potentials, particularly in response to basal dendritic excitation, while the associated evoked firing was significantly reduced. This counterintuitive result was attributed to a marked increase of the rheobase and voltage threshold, indicating a decreased ability to generate spikes in response to depolarizing current. Systemic administration of PCA only slightly altered the ongoing activity of some FP generators, although it produced a striking disengagement of infraslow activities between the cortex and hippocampus on a scale of minutes. To our knowledge, this is the first report showing the direct action of a dietary polyphenol on electrical activity, performing neuromodulatory roles at both the cellular and network levels.

Approximate analytical solution of a (V,m,h) reduced system for backpropagating action potentials in sparsely excitable dendrites

We derive an approximate analytical solution of a nonlinear cable equation describing the backpropagation of action potentials in sparsely excitable dendrites with clusters of transiently activating, TTX-sensitive Na+ channels of low density, discretely distributed as point sources of transmembrane current along a continuous (non-segmented) passive cable structure. Each cluster or hot-spot, corresponding to a mesoscopic level description of Na+ ion channels, included known cumulative inactivation kinetics observed at the microscopic level. In such a reduced third-order system, the ‘recovery’ variable is an electrogenic sodium-pump and/or a Na+-Ca2+ exchanger imbedded in the passive membrane, and a high leakage conductance stabilizes the system. A nonlinear cable equation was used to investigate back-propagation and repetitive activity of action potentials, exhibiting characteristics of the modified Hodgkin-Huxley kinetics (in the presence of suprathreshold input). In particular, a time-dependent analytical solution was obtained through a perturbation expansion of the non-dimensional membrane potential (Φ) for all voltage dependent terms including the voltage dependent Na+ activation μ) and state-dependent inactivation (η) gating variables and then solving the resulting system of integral equations. It was shown that back-propagating action potentials attenuate in amplitude with the frequency following experimental findings and that the discrete and low-density distributions of transient Na+ channels along the cable structure contribute significantly to their discharge patterns. A major significance of integrative modelling is the provision of a continuous description of the non-dimensional membrane potential (Φ) as a function of position.

Differential Control of Small-conductance Calcium-activated Potassium Channel Diffusion by Actin in Different Neuronal Subcompartments.

Small-conductance calcium-activated potassium (SK) channels show a ubiquitous distribution on neurons, in both somatodendritic and axonal regions. SK channels are associated with neuronal activity regulating action potential frequency, dendritic excitability, and synaptic plasticity. Although the physiology of SK channels and the mechanisms that control their surface expression levels have been investigated extensively, little is known about what controls SK channel diffusion in the neuronal plasma membrane. This aspect is important, as the diffusion of SK channels at the surface may control their localization and proximity to calcium channels, hence increasing the likelihood of SK channel activation by calcium. In this study, we successfully investigated the diffusion of SK channels labeled with quantum dots on human embryonic kidney cells and dissociated hippocampal neurons by combining a single-particle tracking method with total internal reflection fluorescence microscopy. We observed that actin filaments interfere with SK mobility, decreasing their diffusion coefficient. We also found that during neuronal maturation, SK channel diffusion was gradually inhibited in somatodendritic compartments. Importantly, we observed that axon barriers formed at approximately days in vitro 6 and restricted the diffusion of SK channels on the axon initial segment (AIS). However, after neuron maturation, SK channels on the AIS were strongly immobilized, even after disruption of the actin network, suggesting that crowding may cause this effect. Altogether, our work provides insight into how SK channels diffuse on the neuronal plasma membrane and how actin and membrane crowding impacts SK channel diffusion.

Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy.

Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed a marked increase in the fraction of hippocampal first-order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 reverses hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.

Synergistic Positive Feedback Mechanisms Underlying Seizure Initiation.

Investigations into seizure initiation, in recent years, have focused almost entirely upon alterations of interneuronal function, chloride homeostasis, and extracellular potassium levels. In contrast, little attention has been directed toward a possible role of dendritic plateau potentials in the actual ictogenic transition, despite a substantial literature dating back 40 years regarding its importance generally in epilepsy. Here, we argue that an increase in dendritic excitability, coordinated across the population of pyramidal cells, is a key stage in ictogenesis.

Computational models reveal how chloride dynamics determine the optimal distribution of inhibitory synapses to minimise dendritic excitability.

Many neurons in the mammalian central nervous system have complex dendritic arborisations and active dendritic conductances that enable these cells to perform sophisticated computations. How dendritically targeted inhibition affects local dendritic excitability is not fully understood. Here we use computational models of branched dendrites to investigate where GABAergic synapses should be placed to minimise dendritic excitability over time. To do so, we formulate a metric we term the "Inhibitory Level" (IL), which quantifies the effectiveness of synaptic inhibition for reducing the depolarising effect of nearby excitatory input. GABAergic synaptic inhibition is dependent on the reversal potential for GABAA receptors (EGABA), which is primarily set by the transmembrane chloride ion (Cl-) concentration gradient. We, therefore, investigated how variable EGABA and dynamic chloride affects dendritic inhibition. We found that the inhibitory effectiveness of dendritic GABAergic synapses combines at an encircled branch junction. The extent of this inhibitory accumulation is dependent on the number of branches and location of synapses but is independent of EGABA. This inhibitory accumulation occurs even for very distally placed inhibitory synapses when they are hyperpolarising-but not when they are shunting. When accounting for Cl- fluxes and dynamics in Cl- concentration, we observed that Cl- loading is detrimental to inhibitory effectiveness. This enabled us to determine the most inhibitory distribution of GABAergic synapses which is close to-but not at-a shared branch junction. This distribution balances a trade-off between a stronger combined inhibitory influence when synapses closely encircle a branch junction with the deleterious effects of increased Cl- by loading that occurs when inhibitory synapses are co-located.

Plasma membrane phospholipid phosphatase-related proteins as pleiotropic regulators of neuron growth and excitability.

Neuronal plasma membrane proteins are essential for integrating cell extrinsic and cell intrinsic signals to orchestrate neuronal differentiation, growth and plasticity in the developing and adult nervous system. Here, we shed light on the family of plasma membrane proteins phospholipid phosphatase-related proteins (PLPPRs) (alternative name, PRGs; plasticity-related genes) that fine-tune neuronal growth and synaptic transmission in the central nervous system. Several studies uncovered essential functions of PLPPRs in filopodia formation, axon guidance and branching during nervous system development and regeneration, as well as in the control of dendritic spine number and excitability. Loss of PLPPR expression in knockout mice increases susceptibility to seizures, and results in defects in sensory information processing, development of psychiatric disorders, stress-related behaviors and abnormal social interaction. However, the exact function of PLPPRs in the context of neurological diseases is largely unclear. Although initially described as active lysophosphatidic acid (LPA) ecto-phosphatases that regulate the levels of this extracellular bioactive lipid, PLPPRs lack catalytic activity against LPA. Nevertheless, they emerge as atypical LPA modulators, by regulating LPA mediated signaling processes. In this review, we summarize the effects of this protein family on cellular morphology, generation and maintenance of cellular protrusions as well as highlight their known neuronal functions and phenotypes of KO mice. We discuss the molecular mechanisms of PLPPRs including the deployment of phospholipids, actin-cytoskeleton and small GTPase signaling pathways, with a focus on identifying gaps in our knowledge to stimulate interest in this understudied protein family.

Acute and protracted abstinence from methamphetamine bidirectionally changes intrinsic excitability of indirect pathway spiny projection neurons in the dorsomedial striatum

Methamphetamine (meth) is an addictive psychostimulant and illicit use presents significant personal and socioeconomic harm. Behavioral studies support the involvement of the dorsal striatum in drug-seeking but stimulant induced dysfunction in this region is understudied. The dorsal striatum can be subdivided into the dorsomedial (DMS) and dorsolateral (DLS) striatum with the DMS implicated in goal-directed and DLS in habitual behaviors; both regions are primarily composed of GABAergic direct (dSPNs) and indirect pathway (iSPNs) spiny projection neurons. To examine the effect of repeated meth on SPNs, mice were administered meth (2 mg/kg) for ten consecutive days and intrinsic excitability, dendritic excitability, and spine density were examined. DMS iSPN intrinsic excitability was increased at 1 day but decreased at 21 days of abstinence. In contrast, DMS dSPN intrinsic excitability was unchanged at either timepoint. Dendritic excitability and spine densities were unaltered in DMS iSPNs and dSPNs at 1 and 21 days of abstinence. The effect of repeated meth on iSPN excitability was specific to the DMS; DLS iSPN intrinsic excitability, dendritic excitability, and spine density were unchanged at 1 and 21 days of abstinence. These findings point toward DMS iSPN dysfunction in meth use disorders with differential dysfunction dependent on abstinence duration.

Non-uniform distribution of dendritic nonlinearities differentially engages thalamostriatal and corticostriatal inputs onto cholinergic interneurons.

The tonic activity of striatal cholinergic interneurons (CINs) is modified differentially by their afferent inputs. Although their unitary synaptic currents are identical, in most CINs cortical inputs onto distal dendrites only weakly entrain them, whereas proximal thalamic inputs trigger abrupt pauses in discharge in response to salient external stimuli. To test whether the dendritic expression of the active conductances that drive autonomous discharge contribute to the CINs' capacity to dissociate cortical from thalamic inputs, we used an optogenetics-based method to quantify dendritic excitability in mouse CINs. We found that the persistent sodium (NaP) current gave rise to dendritic boosting, and that the hyperpolarization-activated cyclic nucleotide-gated (HCN) current gave rise to a subhertz membrane resonance. This resonance may underlie our novel finding of an association between CIN pauses and internally-generated slow wave events in sleeping non-human primates. Moreover, our method indicated that dendritic NaP and HCN currents were preferentially expressed in proximal dendrites. We validated the non-uniform distribution of NaP currents: pharmacologically; with two-photon imaging of dendritic back-propagating action potentials; and by demonstrating boosting of thalamic, but not cortical, inputs by NaP currents. Thus, the localization of active dendritic conductances in CIN dendrites mirrors the spatial distribution of afferent terminals and may promote their differential responses to thalamic vs. cortical inputs.

Light-evoked dendritic spikes in sustained but not transient rabbit retinal ganglion cells

Dendritic computations have a central role in neuronal function, but it is unknown how cell-class heterogeneity of dendritic electrical excitability shapes physiologically engaged neuronal and circuit computations. To address this, we examined dendritic integration in closely related classes of retinal ganglion cells (GCs) using simultaneous somato-dendritic electrical recording techniques in a functionally intact circuit. Simultaneous recordings revealed sustained OFF-GCs generated powerful dendritic spikes in response to visual input that drove action potential firing. In contrast, the dendrites of transient OFF-GCs were passive and did not generate dendritic spikes. Dendritic spike generation allowed sustained, but not transient, OFF-GCs to signal into action potential output the local motion of visual stimuli to produce a continuous wave of action potential firing in adjacent cells as images moved across the retina. Conversely, this representation was highly fragmented in transient OFF-GCs. Thus, a heterogeneity of dendritic excitability defines the computations executed by classes of GCs.