Keeping Your Brain in Balance: Homeostatic Regulation of Network Function.

To perform computations with the efficiency necessary for animal survival, neocortical microcircuits must be capable of reconfiguring in response to experience, while carefully regulating excitatory and inhibitory connectivity to maintain stable function. This dynamic fine-tuning is accomplished through a rich array of cellular homeostatic plasticity mechanisms that stabilize important cellular and network features such as firing rates, information flow, and sensory tuning properties. Further, these functional network properties can be stabilized by different forms of homeostatic plasticity, including mechanisms that target excitatory or inhibitory synapses, or that regulate intrinsic neuronal excitability. Here we discuss which aspects of neocortical circuit function are under homeostatic control, how this homeostasis is realized on the cellular and molecular levels, and the pathological consequences when circuit homeostasis is impaired. A remaining challenge is to elucidate how these diverse homeostatic mechanisms cooperate within complex circuits to enable them to be both flexible and stable.

Basal forebrain cholinergic activity is necessary for upward firing rate homeostasis in the rodent visual cortex.

Bidirectional homeostatic plasticity allows neurons and circuits to maintain stable firing in the face of developmental or learning-induced perturbations. In the primary visual cortex (V1), upward firing rate homeostasis (FRH) only occurs during active wake (AW) and downward during sleep, but how this behavioral state-dependent gating is accomplished is unknown. Here, we focus on how AW enables upward FRH in V1 of juvenile Long Evans rats. A major difference between quiet wake (QW), when upward FRH is absent, and AW, when it is present, is increased cholinergic (ACh) tone, and the main cholinergic projections to V1 arise from the horizontal diagonal band of the basal forebrain (HDB ACh). We therefore chemogenetically inhibited HDB ACh neurons while inducing upward homeostatic compensation using direct activity-suppression in V1. We found that synaptic scaling up and intrinsic homeostatic plasticity, two important cellular mediators of upward FRH, were both impaired when HDB ACh neurons were inhibited. Most strikingly, HDB ACh inhibition flipped the sign of intrinsic plasticity so that it became anti-homeostatic, and this effect was phenocopied by knockdown of the M1 ACh receptor in V1, indicating that this modulation of intrinsic plasticity is the result of direct actions of ACh within V1. Finally, we found that upward FRH induced by visual deprivation was completely prevented by HDB ACh inhibition. Together, our results show that HDB ACh modulation is a key enabler of upward homeostatic plasticity and FRH, and more broadly suggest that neuromodulatory inputs can segregate upward and downward homeostatic plasticity into distinct behavioral states.

Plasticity mechanisms of genetically distinct Purkinje cells.

Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms.

Static Magnetic Field Stimulation Enhances Shunting Inhibition via a SLC26 Family Cl- Channel, Inducing Intrinsic Plasticity.

Magnetic fields are being used for detailed anatomical and functional examination of the human brain. In addition, evidence for their efficacy in treatment of brain dysfunctions is accumulating. Transcranial static magnetic field stimulation (tSMS) is a recently developed technique for noninvasively modifying brain functions. In tSMS, a strong and small magnet when placed over the skull can temporarily suppress brain functions. Its modulatory effects persist beyond the time of stimulation. However, the neurophysiological mechanisms underlying tSMS-induced plasticity remain unclear. Here, using acute motor cortical slice preparation obtained from male C57BL/6N mice, we show that tSMS alters the intrinsic electrical properties of neurons by altering the activity of chloride (Cl-) channels in neurons. Exposure of mouse pyramidal neurons to a static magnetic field (SMF) at a strength similar to human tSMS temporarily decreased their excitability and induced transient neuronal swelling. The effects of SMF were blocked by DIDS and GlyH-101, but not by NPPB, consistent with the pharmacological profile of SLC26A11, a transporter protein with Cl- channel activity. Whole-cell voltage-clamp recordings of the GlyH-101-sensitive Cl- current component showed significant enhancement of the component at both subthreshold and depolarized membrane potentials after SMF application, resulting in shunting inhibition and reduced repetitive action potential (AP) firing at the respective potentials. Thus, this study provides the first neurophysiological evidence for the inhibitory effect of tSMS on neuronal activity and advances our mechanistic understanding of noninvasive human neuromodulation.

Theta patterns of stimulation induce synaptic and intrinsic potentiation in O-LM interneurons.

Brain oscillations have long-lasting effects on synaptic and cellular properties. For instance, synaptic stimulation at theta (θ) frequency induces persistent depression of both excitatory synaptic transmission and intrinsic excitability in CA1 principal neurons. However, the incidence of θ activity on synaptic transmission and intrinsic excitability in hippocampal GABAergic interneurons is unclear. We report here the induction of both synaptic and intrinsic potentiation in oriens-lacunosum moleculare (O-LM) interneurons following stimulation of afferent glutamatergic inputs in the θ frequency range (∼5 Hz). Long-term synaptic potentiation (LTP) is induced by synaptic activation of calcium-permeable AMPA receptors (CP-AMPAR), whereas long-term potentiation of intrinsic excitability (LTP-IE) results from the mGluR1-dependent down-regulation of Kv7 voltage-dependent potassium channel and hyperpolarization activated and cyclic nucleotide-gated (HCN) channel through the depletion of phosphatidylinositol-4,5-biphosphate (PIP2). LTP and LTP-IE are reversible, demonstrating that both synaptic and intrinsic changes are bidirectional in O-LM cells. We conclude that synaptic activity at θ frequency induces both synaptic and intrinsic potentiation in O-LM interneurons, i.e., the opposite of what is typically seen in glutamatergic neurons.

A Role for KCNQ Channels on Cell Type-Specific Plasticity in Mouse Auditory Cortex after Peripheral Damage.

Damage to sensory organs triggers compensatory plasticity mechanisms in sensory cortices. These plasticity mechanisms result in restored cortical responses, despite reduced peripheral input, and contribute to the remarkable recovery of perceptual detection thresholds to sensory stimuli. Overall, peripheral damage is associated with a reduction of cortical GABAergic inhibition; however, less is known about changes in intrinsic properties and the underlying biophysical mechanisms. To study these mechanisms, we used a model of noise-induced peripheral damage in male and female mice. We uncovered a rapid, cell type-specific reduction in the intrinsic excitability of parvalbumin-expressing neurons (PVs) in layer (L) 2/3 of auditory cortex. No changes in the intrinsic excitability of either L2/3 somatostatin-expressing or L2/3 principal neurons (PNs) were observed. The decrease in L2/3 PV excitability was observed 1, but not 7, d after noise exposure, and was evidenced by a hyperpolarization of the resting membrane potential, depolarization of the action potential threshold, and reduction in firing frequency in response to depolarizing current. To uncover the underlying biophysical mechanisms, we recorded potassium currents. We found an increase in KCNQ potassium channel activity in L2/3 PVs of auditory cortex 1 d after noise exposure, associated with a hyperpolarizing shift in the minimal voltage activation of KCNQ channels. This increase contributes to the decreased intrinsic excitability of PVs. Our results highlight cell-type- and channel-specific mechanisms of plasticity after noise-induced hearing loss and will aid in understanding the pathologic processes involved in hearing loss and hearing loss-related disorders, such as tinnitus and hyperacusis.SIGNIFICANCE STATEMENT Noise-induced damage to the peripheral auditory system triggers central plasticity that compensates for the reduced peripheral input. The mechanisms of this plasticity are not fully understood. In the auditory cortex, this plasticity likely contributes to the recovery of sound-evoked responses and perceptual hearing thresholds. Importantly, other functional aspects of hearing do not recover, and peripheral damage may also lead to maladaptive plasticity-related disorders, such as tinnitus and hyperacusis. Here, after noise-induced peripheral damage, we highlight a rapid, transient, and cell type-specific reduction in the excitability of layer 2/3 parvalbumin-expressing neurons, which is due, at least in part, to increased KCNQ potassium channel activity. These studies may highlight novel strategies for enhancing perceptual recovery after hearing loss and mitigating hyperacusis and tinnitus.

Intrinsic threshold plasticity: cholinergic activation and role in the neuronal recognition of incomplete input patterns.

Activity-dependent changes in membrane excitability are observed in neurons across brain areas and represent a cell-autonomous form of plasticity (intrinsic plasticity; IP) that in itself does not involve alterations in synaptic strength (synaptic plasticity; SP). Non-homeostatic IP may play an essential role in learning, e.g. by changing the action potential threshold near the soma. A computational problem, however, arises from the implication that such amplification does not discriminate between synaptic inputs and therefore may reduce the resolution of input representation. Here, we investigate consequences of IP for the performance of an artificial neural network in (a) the discrimination of unknown input patterns and (b) the recognition of known/learned patterns. While negative changes in threshold potentials in the output layer indeed reduce its ability to discriminate patterns, they benefit the recognition of known but incompletely presented patterns. An analysis of thresholds and IP-induced threshold changes in published sets of physiological data obtained from whole-cell patch-clamp recordings from L2/3 pyramidal neurons in (a) the primary visual cortex (V1) of awake macaques and (b) the primary somatosensory cortex (S1) of mice in vitro, respectively, reveals a difference between resting and threshold potentials of ∼15 mV for V1 and ∼25 mV for S1, and a total plasticity range of ∼10 mV (S1). The most efficient activity pattern to lower threshold is paired cholinergic and electric activation. Our findings show that threshold reduction promotes a shift in neural coding strategies from accurate faithful representation to interpretative assignment of input patterns to learned object categories. KEY POINTS: Intrinsic plasticity may change the action potential threshold near the soma of neurons (threshold plasticity), thus altering the input-output function for all synaptic inputs 'upstream' of the plasticity location. A potential problem arising from this shared amplification is that it may reduce the ability to discriminate between different input patterns. Here, we assess the performance of an artificial neural network in the discrimination of unknown input patterns as well as the recognition of known patterns subsequent to changes in the spike threshold. We observe that negative changes in threshold potentials do reduce discrimination performance, but at the same time improve performance in an object recognition task, in particular when patterns are incompletely presented. Analysis of whole-cell patch-clamp recordings from pyramidal neurons in the primary somatosensory cortex (S1) of mice reveals that negative threshold changes preferentially result from electric stimulation of neurons paired with the activation of muscarinic acetylcholine receptors.

The study of plasticity has always been about gradients.

The experimental study of learning and plasticity has always been driven by an implicit question: how can physiological changes be adaptive and improve performance? For example, in Hebbian plasticity only synapses from presynaptic neurons that were active are changed, avoiding useless changes. Similarly, in dopamine-gated learning synapse changes depend on reward or lack thereof and do not change when everything is predictable. Within machine learning we can make the question of which changes are adaptive concrete: performance improves when changes correlate with the gradient of an objective function quantifying performance. This result is general for any system that improves through small changes. As such, physiology has always implicitly been seeking mechanisms that allow the brain to approximate gradients. Coming from this perspective we review the existing literature on plasticity-related mechanisms, and we show how these mechanisms relate to gradient estimation. We argue that gradients are a unifying idea to explain the many facets of neuronal plasticity.

The enigmatic HCN channels: A cellular neurophysiology perspective.

What physiological role does a slow hyperpolarization-activated ion channel with mixed cation selectivity play in the fast world of neuronal action potentials that are driven by depolarization? That puzzling question has piqued the curiosity of physiology enthusiasts about the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are widely expressed across the body and especially in neurons. In this review, we emphasize the need to assess HCN channels from the perspective of how they respond to time-varying signals, while also accounting for their interactions with other co-expressing channels and receptors. First, we illustrate how the unique structural and functional characteristics of HCN channels allow them to mediate a slow negative feedback loop in the neurons that they express in. We present the several physiological implications of this negative feedback loop to neuronal response characteristics including neuronal gain, voltage sag and rebound, temporal summation, membrane potential resonance, inductive phase lead, spike triggered average, and coincidence detection. Next, we argue that the overall impact of HCN channels on neuronal physiology critically relies on their interactions with other co-expressing channels and receptors. Interactions with other channels allow HCN channels to mediate intrinsic oscillations, earning them the "pacemaker channel" moniker, and to regulate spike frequency adaptation, plateau potentials, neurotransmitter release from presynaptic terminals, and spike initiation at the axonal initial segment. We also explore the impact of spatially non-homogeneous subcellular distributions of HCN channels in different neuronal subtypes and their interactions with other channels and receptors. Finally, we discuss how plasticity in HCN channels is widely prevalent and can mediate different encoding, homeostatic, and neuroprotective functions in a neuron. In summary, we argue that HCN channels form an important class of channels that mediate a diversity of neuronal functions owing to their unique gating kinetics that made them a puzzle in the first place.

Homeostatic mechanisms regulate distinct aspects of cortical circuit dynamics.

Homeostasis is indispensable to counteract the destabilizing effects of Hebbian plasticity. Although it is commonly assumed that homeostasis modulates synaptic strength, membrane excitability, and firing rates, its role at the neural circuit and network level is unknown. Here, we identify changes in higher-order network properties of freely behaving rodents during prolonged visual deprivation. Strikingly, our data reveal that functional pairwise correlations and their structure are subject to homeostatic regulation. Using a computational model, we demonstrate that the interplay of different plasticity and homeostatic mechanisms can capture the initial drop and delayed recovery of firing rates and correlations observed experimentally. Moreover, our model indicates that synaptic scaling is crucial for the recovery of correlations and network structure, while intrinsic plasticity is essential for the rebound of firing rates, suggesting that synaptic scaling and intrinsic plasticity can serve distinct functions in homeostatically regulating network dynamics.

Cell Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism.

The hypokinetic motor symptoms of Parkinson's disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine (DA) alters the cellular properties of motor cortical neurons in PD remains undefined. We induced parkinsonism in adult C57BL/6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the primary motor cortical (M1) layer (L)5b was greatly decreased in parkinsonism; but the intratelencephalic neurons (ITNs) were not affected. The cell type-specific intrinsic adaptations were associated with a depolarized threshold and broadened width of action potentials (APs) in PTNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which could underlie their abnormal pattern of activity in the parkinsonian state. We also showed that the decreased excitability in parkinsonism was caused by an impaired function of both persistent sodium channels and the large conductance, Ca2+-activated K+ channels. Acute activation of dopaminergic receptors failed to rescue the impaired intrinsic excitability of M1 PTNs in parkinsonian mice. Altogether, our data demonstrated a cell type-specific decrease of the excitability of M1 pyramidal neurons in parkinsonism. Thus, intrinsic adaptations in the motor cortex provide novel insight in our understanding of the pathophysiology of motor deficits in PD.SIGNIFICANCE STATEMENT The degeneration of midbrain dopaminergic neurons in Parkinson's disease (PD) remodels the connectivity and function of cortico-basal ganglia-thalamocortical network. However, whether and how dopaminergic degeneration and the associated basal ganglia dysfunction alter motor cortical circuitry remain undefined. We found that pyramidal neurons in the layer (L)5b of the primary motor cortex (M1) exhibit distinct adaptations in response to the loss of midbrain dopaminergic neurons, depending on their long-range projections. Besides the decreased thalamocortical synaptic excitation as proposed by the classical model of Parkinson's pathophysiology, these results, for the first time, show novel cellular and molecular mechanisms underlying the abnormal motor cortical output in parkinsonism.

Endocannabinoids Tune Intrinsic Excitability in O-LM Interneurons by Direct Modulation of Postsynaptic Kv7 Channels.

KCNQ-Kv7 channels are found at the axon initial segment of pyramidal neurons, where they control cell firing and membrane potential. In oriens lacunosum moleculare (O-LM) interneurons, these channels are mainly expressed in the dendrites, suggesting a peculiar function of Kv7 channels in these neurons. Here, we show that Kv7 channel activity is upregulated following induction of presynaptic long-term synaptic depression (LTD) in O-LM interneurons from rats of both sex, thus resulting in a synergistic long-term depression of intrinsic excitability (LTD-IE). Both LTD and LTD-IE involve endocannabinoid (eCB) biosynthesis for induction. However, although LTD is dependent on cannabinoid type 1 receptors, LTD-IE is not. Molecular modeling shows a strong interaction of eCBs with Kv7.2/3 channel, suggesting a persistent action of these lipids on Kv7 channel activity. Our data thus unveil a major role for eCB synthesis in triggering both synaptic and intrinsic depression in O-LM interneurons.SIGNIFICANCE STATEMENT In principal cells, Kv7 channels are essentially located at the axon initial segment. In contrast, in O-LM interneurons, Kv7 channels are highly expressed in the dendrites, suggesting a singular role of these channels in O-LM cell function. Here, we show that LTD of excitatory inputs in O-LM interneurons is associated with an upregulation of Kv7 channels, thus resulting in a synergistic LTD of LTD-IE. Both forms of plasticity are mediated by the biosynthesis of eCBs. Stimulation of CB1 receptors induces LTD, whereas the direct interaction of eCBs with Kv7 channels induces LTD-IE. Our results thus provide a previously unexpected involvement of eCBs in long-lasting plasticity of intrinsic excitability in GABAergic interneurons.

Parvalbumin subtypes of cerebellar Purkinje cells contribute to differential intrinsic firing properties.

Purkinje cells (PCs) are central to cerebellar information coding and appreciation for the diversity of their firing patterns and molecular profiles is growing. Heterogeneous subpopulations of PCs have been identified that display differences in intrinsic firing properties without clear mechanistic insight into what underlies the divergence in firing parameters. Although long used as a general PC marker, we report that the calcium binding protein parvalbumin labels a subpopulation of PCs, based on high and low expression, with a conserved distribution pattern across the animals examined. We trained a convolutional neural network to recognize the parvalbumin subtypes and create maps of whole cerebellar distribution and find that PCs within these areas have differences in spontaneous firing that can be modified by altering calcium buffer content. These subtypes also show differential responses to potassium and calcium channel blockade, suggesting a mechanistic role for variability in PC intrinsic firing through differences in ion channel composition. It is proposed that ion channels drive the diversity in PC intrinsic firing phenotype and parvalbumin calcium buffering provides capacity for the highest firing rates observed. These findings open new avenues for detailed classification of PC subtypes.

Experience- and Sex-Dependent Intrinsic Plasticity in the Zebra Finch Auditory Cortex during Song Memorization.

For vocal communicators like humans and songbirds, survival and reproduction depend on highly developed auditory processing systems that can detect and differentiate nuanced differences in vocalizations, even amid noisy environments. Early auditory experience is critical to the development of these systems. In zebra finches and other songbirds, there is a sensitive period when young birds memorize a song that will serve as a model for their own vocal production. In addition to learning a specific tutor's song, the auditory system may also undergo critical developmental processes that support auditory perception of vocalizations more generally. Here, we investigate changes in intrinsic spiking dynamics among neurons in the caudal mesopallium, a cortical-level auditory area implicated in discriminating and learning species-specific vocalizations. A subset of neurons in this area only fire transiently at the onset of current injections (i.e., phasic firing), a dynamical property that can enhance the reliability and selectivity of neural responses to complex acoustic stimuli. At the beginning of the sensitive period, just after zebra finches have fledged from the nest, there is an increase in the proportion of caudal mesopallium neurons with phasic excitability, and in the proportion of neurons expressing Kv1.1, a low-threshold channel that facilitates phasic firing. This plasticity requires exposure to a complex, noisy environment and is greater in males, the only sex that sings in this species. This shift to more phasic dynamics is therefore an experience-dependent adaptation that could facilitate auditory processing in noisy, acoustically complex conditions during a key stage of vocal development.SIGNIFICANCE STATEMENT Auditory experience early in life shapes how humans and songbirds perceive the vocal communication sounds produced by their species. However, the changes that occur in the brain as this learning takes place are poorly understood. In this study, we show that in young zebra finches that are just beginning to learn the structure of their species' song, neurons in a key cortical area adapt their intrinsic firing patterns in response to the acoustic environment. In the complex, cocktail-party-like environment of a colony, more neurons adopt transient firing dynamics, which can facilitate neural coding of songs amid such challenging conditions.

Modification of Synaptic-Input Clustering by Intrinsic Excitability Plasticity on Cerebellar Purkinje Cell Dendrites.

The role of dendrites in the integration of widespread synaptic activity has been studied in experiments and theories (Johnston et al., 1996; Magee, 2007). However, whether the conduction of synaptic currents from dendrites to the soma depends on excitability of those dendritic branches is unclear. How modulation of the branch excitability affects the conduction of synaptic inputs and their selection on dendrites is also elusive. Here, I performed simultaneous voltage-clamp recordings from the soma and dendrites of single cerebellar Purkinje neurons in male Sprague-Dawley rats and analyzed the relationship between spontaneous EPSCs on both sides. I found that EPSCs on distal dendrites have a salient discordance in amplitude compared with those on the soma. Furthermore, individual ratios of the EPSC concurrently recorded on the soma and dendrites were not unique, but discrete, suggesting the occurrence of various attenuations in different paths of dendritic branches to the soma. The obtained data and simulations indicate several distinct groups (4.5 ± 0.3, n = 22 somatodendritic recordings) of co-occurred synaptic inputs in Purkinje cell dendrites. This clustering of synaptic currents was suggested to emerge at farther distances than the secondary bifurcations. Finally, ratios of the co-EPSCs were uniformly distributed after either intrinsic plasticity induction or SK-channel blockade. Overall, results suggest that in Purkinje cells the excitability along the dendrite processes modulates the conduction of EPSCs and makes active inputs heterogeneous through SK channel activity, intrinsic plasticity, and dendritic branching. These properties of dendrites may confer branch-specific computational power to neurons.SIGNIFICANCE STATEMENT I have previously studied the "non-synaptic" plasticity of the intrinsic excitability in the cerebellar Purkinje cells (Belmeguenai et al., 2010), and branch-specific increase of intrinsic excitability of the dendrites (Ohtsuki et al., 2012b; Ohtsuki and Hansel, 2018) through the downregulation of SK (small conductance Ca2+-activated K+) channels. In this study, I show that a dendritic filtering of synaptic electroconductivity is heterogeneous among the branches on distal dendrites and that the increase in the dendritic excitability accompanied with the intrinsic plasticity alters a state with the heterogeneity to a globally excitable state in Purkinje neurons. My findings propose a new learning model relying on the intrinsic excitability plasticity of the dendritic branch fields.

Intrinsic Plasticity of Cerebellar Purkinje Cells Contributes to Motor Memory Consolidation.

Intrinsic plasticity of cerebellar Purkinje cells (PCs) has recently been demonstrated in cerebellar local circuits; however, its physiological impact on cerebellar learning and memory remains elusive. Here, we suggest that intrinsic plasticity of PCs is tightly involved in motor memory consolidation based on findings from PC-specific STIM1 knockout male mice, which show severe memory consolidation deficiency in vestibulo-ocular reflex memory. Gain-up training of the vestibulo-ocular reflex produced a decrease in the synaptic weight of PCs in both the WT and KO groups. However, intrinsic plasticity was impaired only in the knockout mice. Furthermore, the observed defects in the intrinsic plasticity of PCs led to the formation of aberrant neural plasticity in the vestibular nucleus neurons. Our results suggest that synergistic modulation of intrinsic and synaptic plasticity in PCs is required for the changes in downstream plasticity in the vestibular nucleus, and thereby contributing to the long-term storage of motor memory.SIGNIFICANCE STATEMENT Synaptic plasticity is a well-known mechanism for learning and memory. Although plasticity of excitability, intrinsic plasticity, of the cerebellar Purkinje cell has been reported in both directions (potentiation and depression), the physiological role of intrinsic plasticity still remains ambiguous. In this study, we suggest that both synaptic and intrinsic plasticity are required for successful memory consolidation in cerebellar eye movement learning. Despite successful induction and maintenance of synaptic plasticity, we found deficits of memory consolidation when there were defects in intrinsic plasticity. Our results suggest that intrinsic plasticity of cerebellar Purkinje cell has a significant role in motor memory consolidation.

Intracellular Zn2+ Signaling Facilitates Mossy Fiber Input-Induced Heterosynaptic Potentiation of Direct Cortical Inputs in Hippocampal CA3 Pyramidal Cells.

Repetitive action potentials (APs) in hippocampal CA3 pyramidal cells (CA3-PCs) backpropagate to distal apical dendrites, and induce calcium and protein tyrosine kinase (PTK)-dependent downregulation of Kv1.2, resulting in long-term potentiation of direct cortical inputs and intrinsic excitability (LTP-IE). When APs were elicited by direct somatic stimulation of CA3-PCs from rodents of either sex, only a narrow window of distal dendritic [Ca2+] allowed LTP-IE because of Ca2+-dependent coactivation of PTK and protein tyrosine phosphatase (PTP), which renders non-mossy fiber (MF) inputs incompetent in LTP-IE induction. High-frequency MF inputs, however, could induce LTP-IE at high dendritic [Ca2+] of the window. We show that MF input-induced Zn2+ signaling inhibits postsynaptic PTP, and thus enables MF inputs to induce LTP-IE at a wide range of [Ca2+]i values. Extracellular chelation of Zn2+ or genetic deletion of vesicular zinc transporter abrogated the privilege of MF inputs for LTP-IE induction. Moreover, the incompetence of somatic stimulation was rescued by the inhibition of PTP or a supplement of extracellular zinc, indicating that MF input-induced increase in dendritic [Zn2+] facilitates the induction of LTP-IE by inhibiting PTP. Consistently, high-frequency MF stimulation induced immediate and delayed elevations of [Zn2+] at proximal and distal dendrites, respectively. These results indicate that MF inputs are uniquely linked to the regulation of direct cortical inputs owing to synaptic Zn2+ signaling.SIGNIFICANCE STATEMENT Zn2+ has been mostly implicated in pathological processes, and the physiological roles of synaptically released Zn2+ in intracellular signaling are little known. We show here that Zn2+ released from hippocampal mossy fiber (MF) terminals enters postsynaptic CA3 pyramidal cells, and plays a facilitating role in MF input-induced heterosynaptic potentiation of perforant path (PP) synaptic inputs through long-term potentiation of intrinsic excitability (LTP-IE). We show that the window of cytosolic [Ca2+] that induces LTP-IE is normally very narrow because of the Ca2+-dependent coactivation of antagonistic signaling pairs, whereby non-MF inputs become ineffective in inducing excitability change. The MF-induced Zn2+ signaling, however, biases toward facilitating the induction of LTP-IE. The present study elucidates why MF inputs are more privileged for the regulation of PP synapses.

Experience-Dependent Intrinsic Plasticity During Auditory Learning.

Song learning in zebra finches (Taeniopygia guttata) requires exposure to the song of a tutor, resulting in an auditory memory. This memory is the foundation for later sensorimotor learning, resulting in the production of a copy of the tutor's song. The cortical premotor nucleus HVC (proper name) is necessary for auditory and sensorimotor learning as well as the eventual production of adult song. We recently discovered that the intrinsic physiology of HVC neurons changes across stages of song learning, but are those changes the result of learning or are they experience-independent developmental changes? To test the role of auditory experience in driving intrinsic changes, patch-clamp experiments were performed comparing HVC neurons in juvenile birds with varying amounts of tutor exposure. The intrinsic physiology of HVC neurons changed as a function of tutor exposure. Counterintuitively, tutor deprivation resulted in juvenile HVC neurons showing an adult-like phenotype not present in tutor-exposed juveniles. Biophysical models were developed to predict which ion channels were modulated by experience. The models indicate that tutor exposure transiently suppressed the Ih and T-type Ca2+ currents in HVC neurons that target the basal ganglia, whereas tutor exposure increased the resting membrane potential and decreased the spike amplitude in HVC neurons that drive singing. Our findings suggest that intrinsic plasticity may be part of the mechanism for auditory learning in the HVC. More broadly, models of learning and memory should consider intrinsic plasticity as a possible mechanism by which the nervous system encodes the lasting effects of experience.SIGNIFICANCE STATEMENT It is well established that learning involves plasticity of the synapses between neurons. However, the activity of a neural circuit can also be dramatically altered by changes in the intrinsic properties (ion channels) of the component neurons. The present experiments show experience-dependent changes in the intrinsic physiology of neurons in the cortical premotor nucleus HVC (proper name) in juvenile zebra finches (Taeniopygia guttata) during auditory learning of a tutor's song. Tutor deprivation does not "arrest" development of intrinsic properties, but rather results in neurons with a premature adult-like physiological phenotype. It is possible that auditory learning involves a form of nonsynaptic plasticity and that experience-dependent suppression of specific ion channels may work in concert with synaptic plasticity to promote vocal learning.

Conditioning by subthreshold synaptic input changes the intrinsic firing pattern of CA3 hippocampal neurons.

Unlike synaptic strength, intrinsic excitability is assumed to be a stable property of neurons. For example, learning of somatic conductances is generally not incorporated into computational models, and the discharge pattern of neurons in response to test stimuli is frequently used as a basis for phenotypic classification. However, it is increasingly evident that signal processing properties of neurons are more generally plastic on the timescale of minutes. Here we demonstrate that the intrinsic firing patterns of CA3 neurons of the rat hippocampus in vitro undergo rapid long-term plasticity in response to a few minutes of only subthreshold synaptic conditioning. This plasticity on the spike timing could also be induced by intrasomatic injection of subthreshold depolarizing pulses and was blocked by kinase inhibitors, indicating that discharge dynamics are modulated locally. Cluster analysis of firing patterns before and after conditioning revealed systematic transitions toward adapting and intrinsic burst behaviors, irrespective of the patterns initially exhibited by the cells. We used a conductance-based model to decide appropriate pharmacological blockade and found that the observed transitions are likely due to recruitment of low-voltage calcium and Kv7 potassium conductances. We conclude that CA3 neurons adapt their conductance profile to the subthreshold activity of their input, so that their intrinsic firing pattern is not a static signature, but rather a reflection of their history of subthreshold activity. In this way, recurrent output from CA3 neurons may collectively shape the temporal dynamics of their embedding circuits.NEW & NOTEWORTHY Although firing patterns are widely conserved across the animal phyla, it is still a mystery why nerve cells present such diversity of discharge dynamics upon somatic step currents. Adding a new timing dimension to the intrinsic plasticity literature, here we show that CA3 neurons rapidly adapt through the space of known firing patterns in response to the subthreshold signals that they receive from their embedding circuit, potentially adjusting their network processing to the temporal statistics of their circuit.

Modulation of intrinsic excitability as a function of learning within the fear conditioning circuit.

Experience-dependent neuronal plasticity is a fundamental substrate of learning and memory. Intrinsic excitability is a form of neuronal plasticity that can be altered by learning and indicates the pattern of neuronal responding to external stimuli (e.g. a learning or synaptic event). Associative fear conditioning is one form of learning that alters intrinsic excitability, reflecting an experience-dependent change in neuronal function. After fear conditioning, intrinsic excitability changes are evident in brain regions that are a critical part of the fear circuit, including the amygdala, hippocampus, retrosplenial cortex, and prefrontal cortex. Some of these changes are transient and/or reversed by extinction as well as learning-specific (i.e. they are not observed in neurons from control animals). This review will explore how intrinsic neuronal excitability changes within brain structures that are critical for fear learning, and it will also discuss evidence promoting intrinsic excitability as a vital mechanism of associative fear memories. This work has raised interesting questions regarding the role of fear learning in changes of intrinsic excitability within specific subpopulations of neurons, including those that express immediate early genes and thus demonstrate experience-dependent activity, as well as in neurons classified as having a specific firing type (e.g. burst-spiking vs. regular-spiking). These findings have interesting implications for how intrinsic excitability can serve as a neural substrate of learning and memory, and suggest that intrinsic plasticity within specific subpopulations of neurons may promote consolidation of the memory trace in a flexible and efficient manner.