Deciphering functional roles of synaptic plasticity and intrinsic neural firing in developing mouse visual cortex layer IV microcircuit.

Between the onset of the critical period of mouse primary visual cortex and eye opening at postnatal day 14 is a complex process and that is vital for the cognitive function of vision. The onset of the critical period of mouse primary visual cortex involves changes of the intrinsic firing property of each neuron and short term plasticity of synapses. In order to investigate the functional role of each factor in regulating the circuit firing activity during the critical period plasticity, we adopted the Markram's model for short term plasticity and Wilson's model for intrinsic neuron firing activity, and construct a microcircuit for mouse visual cortex layer IV based on the connection probabilities from experimental results. Our results indicate that, during CP development, the most critical factors that regulate the firing pattern of microcircuit is the short term plasticity of the synapse from PC to PV and SST interneurons, which upregulates the PV interneuron firing and produces new balance between excitation and inhibition; the intrinsic firing activity of PC and PV during development downregulates the firing frequency of the circuits. In addition, we have investigated the function of feedforward excitatory thalamic-cortical projection to PC and PV interneuron during CP, and found that neural firing activity largely depends on the TC input and the results are similar to the local circuit with minor differences. We conclude that the short term plasticity development during critical period plays a crucial role in regulating the circuit behavior.

Development of synaptic fidelity and action potential robustness at an inhibitory sound localization circuit: effects of otoferlin-related deafness.

Sound localization involves information analysis in the lateral superior olive (LSO), a conspicuous nucleus in the mammalian auditory brainstem. LSO neurons weigh interaural level differences (ILDs) through precise integration of glutamatergic excitation from the cochlear nucleus (CN) and glycinergic inhibition from the medial nucleus of the trapezoid body (MNTB). Sound sources can be localized even during sustained perception, an accomplishment that requires robust neurotransmission. Virtually nothing is known about the sustained performance and the temporal precision of MNTB-LSO inputs after postnatal day (P)12 (time of hearing onset) and whether acoustic experience guides development. Here we performed whole-cell patch-clamp recordings to investigate neurotransmission of single MNTB-LSO fibres upon sustained electrical stimulation (1-200 Hz/60 s) at P11 and P38 in wild-type (WT) and deaf otoferlin (Otof) knock-out (KO) mice. At P11, WT and KO inputs performed remarkably similarly. In WTs, the performance increased drastically between P11 and P38, e.g. manifested by an 8 to 11-fold higher replenishment rate (RR) of synaptic vesicles and action potential robustness. Together, these changes resulted in reliable and highly precise neurotransmission at frequencies ≤100 Hz. In contrast, KO inputs performed similarly at both ages, implying impaired synaptic maturation. Computational modelling confirmed the empirical observations and established a reduced RR per release site for P38 KOs. In conclusion, acoustic experience appears to contribute massively to the development of reliable neurotransmission, thereby forming the basis for effective ILD detection. Collectively, our results provide novel insights into experience-dependent maturation of inhibitory neurotransmission and auditory circuits at the synaptic level. KEY POINTS: Inhibitory glycinergic inputs from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) are involved in sound localization. This brainstem circuit performs reliably throughout life. How such reliability develops is unknown. Here we investigated the role of acoustic experience on the functional maturation of MNTB-LSO inputs at juvenile (postnatal day P11) and young adult ages (P38) employing deaf mice lacking otoferlin (KO). We analysed neurotransmission at single MNTB-LSO fibres in acute brainstem slices employing prolonged high-frequency stimulation (1-200 Hz/60 s). At P11, KO inputs still performed normally, as manifested by normal synaptic attenuation, fidelity, replenishment rate, temporal precision and action potential robustness. Between P11 and P38, several synaptic parameters increased substantially in wild-type mice, collectively resulting in high-fidelity and temporally precise neurotransmission. In contrast, maturation of synaptic fidelity was largely absent in KOs after P11. Collectively, reliable neurotransmission at inhibitory MNTB-LSO inputs develops under the guidance of acoustic experience.

The molecular diversity of plasticity mechanisms underlying memory: An evolutionary perspective.

Experience triggers molecular cascades in organisms (learning) that lead to alterations (memory) to allow the organism to change its behavior based on experience. Understanding the molecular mechanisms underlying memory, particularly in the nervous system of animals, has been an exciting scientific challenge for neuroscience. We review what is known about forms of neuronal plasticity that underlie memory highlighting important issues in the field: (1) the importance of being able to measure how neurons are activated during learning to identify the form of plasticity that underlies memory, (2) the many distinct forms of plasticity important for memories that naturally decay both within and between organisms, and (3) unifying principles underlying the formation and maintenance of long-term memories. Overall, the diversity of molecular mechanisms underlying memories that naturally decay contrasts with more unified molecular mechanisms implicated in long-lasting changes. Despite many advances, important questions remain as to which mechanisms of neuronal plasticity underlie memory.

Neuromodulation of circuits with variable parameters: single neurons and small circuits reveal principles of state-dependent and robust neuromodulation.

Neuromodulation underlies many behavioral states and has been extensively studied in small circuits. This has allowed the systematic exploration of how neuromodulatory substances and the neurons that release them can influence circuit function. The physiological state of a network and its level of activity can have profound effects on how the modulators act, a phenomenon known as state dependence. We provide insights from experiments and computational work that show how state dependence can arise and the consequences it can have for cellular and circuit function. These observations pose a general unsolved question that is relevant to all nervous systems: How is robust modulation achieved in spite of animal-to-animal variability and degenerate, nonlinear mechanisms for the production of neuronal and network activity?

Modulation of information processing by AMPA receptor auxiliary subunits.

AMPA-type glutamate receptors (AMPARs) are key molecules of neuronal communication in our brain. The discovery of AMPAR auxiliary subunits, such as proteins of the TARP, CKAMP and CNIH families, fundamentally changed our understanding of how AMPAR function is regulated. Auxiliary subunits control almost all aspects of AMPAR function in the brain. They influence AMPAR assembly, composition, structure, trafficking, subcellular localization and gating. This influence has important implications for synapse function. In the present review, we first discuss how auxiliary subunits affect the strength of synapses by modulating number and localization of AMPARs in synapses as well as their glutamate affinity, conductance and peak open probability. Next we explain how the presence of auxiliary subunits alters temporal precision and integrative properties of synapses by influencing gating kinetics of the receptors. Auxiliary subunits of the TARP and CKAMP family modulate synaptic short-term plasticity by increasing anchoring of AMPARs in synapses and by altering their desensitization kinetics. We then describe how auxiliary subunits of the TARP, CKAMP and CNIH families are involved in Hebbian and homeostatic plasticity, which can be explained by their influence on surface trafficking and synaptic targeting. In conclusion, the series of studies covered in this review show that auxiliary subunits play a pivotal role in controlling information processing in the brain by modulating synaptic computation.

mGluR5 Facilitates Long-Term Synaptic Depression in a Stress-Induced Depressive Mouse Model.

BACKGROUND: Glutamatergic system has been known to play a role in the pathogenesis of major depression disorder by inducing N-methyl-d-aspartate receptor-dependent long-term depression (LTD) or metabotropic glutamate receptors (mGluR)-dependent LTD. Here, we characterized the LTD in a chronic social defeat stress (CSDS)-induced depressive mouse model. METHODS: CSDS was used to induce the depressive-like behaviors in C57BL/6 male mice, which were assessed using sucrose preference test and social interaction test. The synaptic strength including LTD and long-term potentiation (LTP) induced by paired-pulse low frequency stimulation (PP-LFS) was measured using whole-cell recording technique. RESULTS: CSDS induced depressive-like behaviors and facilitated PP-LFS-induced LTD in hippocampal CA3-CA1 pathway in the susceptible mice. Interestingly, mGluR5 but not N-methyl-d-aspartate receptor mediated the PP-LFS-induced LTD. In addition, mGluR5 agonist dihydroxyphenylglycine promoted PP-LFS-induced LTD specifically in susceptible mice, which was diminished by activating the BDNF/TrkB signaling pathway. CONCLUSIONS: Our results suggest that mGluR5-dependent LTD might be responsible for the development of depressive-like behaviors in CSDS-induced depression mice model.

Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity.

KEY POINTS: Loss of the calcium sensor otoferlin disrupts neurotransmission from inner hair cells. Central auditory nuclei are functionally denervated in otoferlin knockout mice (Otof KOs) via gene ablation confined to the periphery. We employed juvenile and young adult Otof KO mice (postnatal days (P)10-12 and P27-49) as a model for lacking spontaneous activity and deafness, respectively. We studied the impact of peripheral activity on synaptic refinement in the sound localization circuit from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO). MNTB in vivo recordings demonstrated drastically reduced spontaneous spiking and deafness in Otof KOs. Juvenile KOs showed impaired synapse elimination and strengthening, manifested by broader MNTB-LSO inputs, imprecise MNTB-LSO topography and weaker MNTB-LSO fibres. The impairments persisted into young adulthood. Further functional refinement after hearing onset was undetected in young adult wild-types. Collectively, activity deprivation confined to peripheral protein loss impairs functional MNTB-LSO refinement during a critical prehearing period. ABSTRACT: Circuit refinement is critical for the developing sound localization pathways in the auditory brainstem. In prehearing mice (hearing onset around postnatal day (P)12), spontaneous activity propagates from the periphery to central auditory nuclei. At the glycinergic projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) of neonatal mice, super-numerous MNTB fibres innervate a given LSO neuron. Between P4 and P9, MNTB fibres are functionally eliminated, whereas the remaining fibres are strengthened. Little is known about MNTB-LSO circuit refinement after P20. Moreover, MNTB-LSO refinement upon activity deprivation confined to the periphery is largely unexplored. This leaves a considerable knowledge gap, as deprivation often occurs in patients with congenital deafness, e.g. upon mutations in the otoferlin gene (OTOF). Here, we analysed juvenile (P10-12) and young adult (P27-49) otoferlin knockout (Otof KO) mice with respect to MNTB-LSO refinement. MNTB in vivo recordings revealed drastically reduced spontaneous activity and deafness in knockouts (KOs), confirming deprivation. As RNA sequencing revealed Otof absence in the MNTB and LSO of wild-types, Otof loss in KOs is specific to the periphery. Functional denervation impaired MNTB-LSO synapse elimination and strengthening, which was assessed by glutamate uncaging and electrical stimulation. Impaired elimination led to imprecise MNTB-LSO topography. Impaired strengthening was associated with lower quantal content per MNTB fibre. In young adult KOs, the MNTB-LSO circuit remained unrefined. Further functional refinement after P12 appeared absent in wild-types. Collectively, we provide novel insights into functional MNTB-LSO circuit maturation governed by a cochlea-specific protein. The central malfunctions in Otof KOs may have implications for patients with sensorineuronal hearing loss.

Action potentials and subthreshold potentials of dorsal horn neurons in a rat model of myositis: a study employing intracellular recordings in vivo.

Intracellular in vivo recordings from rat dorsal horn neurons were made to study the contribution of microglia to the central sensitization of spinal synapses induced by a chronic muscle inflammation. To block microglia activation, minocycline was continuously administered intrathecally during development of the inflammation. The aim was to test whether an inflammation-induced sensitization of dorsal horn neurons is mediated by changes in synaptic strength or other synaptic changes and how activated microglia influence these processes. Intracellular recordings were used to measure subthreshold excitatory postsynaptic potentials (EPSPs) and suprathreshold action potentials (APs). The muscle inflammation significantly increased the proportion of dorsal horn neurons responding with APs or EPSPs to electrical stimulation of the muscle nerve from 27 to 56% (P < 0.01) and to noxious muscle stimulation (3 vs. 44%, P < 0.01). Neurons showing spontaneous ongoing AP or EPSP activity increased from 28 to 74% (P < 0.01). Generally, the increases in suprathreshold AP responses did not occur at the expense of subthreshold EPSPs, because EPSP-only responses also increased. Intrathecal minocycline prevented the inflammation-induced increase in responsiveness to electrical (24%, P < 0.02) and mechanical stimulation (14%, P < 0.02); the effect was stronger on suprathreshold APs than on subthreshold EPSPs. The increase in ongoing activity was only partly suppressed. These data suggest that the myositis-induced hypersensitivity of the dorsal horn neurons to peripheral input and its prevention by intrathecal minocycline treatment were due to both an increase in the number of active synapses and an increased synaptic strength.NEW & NOTEWORTHY During a chronic muscle inflammation (myositis), activated microglia controls both the increase in the number of active synapses and the increase in synaptic strength.

Effects of slow-wave activity on mood disturbance in major depressive disorder.

BACKGROUND: Studies have demonstrated that decreases in slow-wave activity (SWA) predict decreases in depressive symptoms in those with major depressive disorder (MDD), suggesting that there may be a link between SWA and mood. The aim of the present study was to determine if the consequent change in SWA regulation following a mild homeostatic sleep challenge would predict mood disturbance. METHODS: Thirty-seven depressed and fifty-nine healthy adults spent three consecutive nights in the sleep laboratory. On the third night, bedtime was delayed by 3 h, as this procedure has been shown to provoke SWA. The Profile of Mood States questionnaire was administered on the morning following the baseline and sleep delay nights to measure mood disturbance. RESULTS: Results revealed that following sleep delay, a lower delta sleep ratio, indicative of inadequate dissipation of SWA from the first to the second non-rapid eye movement period, predicted increased mood disturbance in only those with MDD. CONCLUSIONS: These data demonstrate that in the first half of the night, individuals with MDD who have less SWA dissipation as a consequence of impaired SWA regulation have greater mood disturbance, and may suggest that appropriate homeostatic regulation of sleep is an important factor in the disorder.

An Integrated Model of Slow-Wave Activity and Neuroplasticity Impairments in Major Depressive Disorder.

PURPOSE OF REVIEW: In this review, we aim to integrate the most recent research highlighting alterations in sleep slow-wave activity (SWA), and impairments in neuroplasticity in major depressive disorder (MDD) into a novel model of disorder maintenance. RECENT FINDINGS: Sleep homeostasis has been shown to be impaired in MDD, with a subset of individuals also demonstrating impaired SWA. SWA is considered a marker of the homeostatic regulation of sleep, and is implicated in the downscaling of synaptic strength in the context of maintaining homeostatic plasticity. Individuals with MDD have been shown to exhibit impairments in both neural plasticity such as loss of dendritic branching, and synaptic plasticity such as decreased long-term potentiation-dependent learning and memory. Alterations in the homeostatic regulation of sleep, SWA, and synaptic plasticity in MDD suggest an underlying impairment in the modulation of synaptic strength. One candidate mechanism for this impairment is AMPA receptor trafficking.

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks.

Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-d-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca(2+) signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca(2+) channels. Intracellular infusion of NMDARs or Ca(2+)-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocyte-dependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites.

Hair cells use active zones with different voltage dependence of Ca2+ influx to decompose sounds into complementary neural codes.

For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range of audible sound pressures. Heterogeneity of synapses between inner hair cells (IHCs) and SGNs is an attractive candidate mechanism for generating complementary neural codes covering the entire dynamic range. Here, we quantified active zone (AZ) properties as a function of AZ position within mouse IHCs by combining patch clamp and imaging of presynaptic Ca(2+) influx and by immunohistochemistry. We report substantial AZ heterogeneity whereby the voltage of half-maximal activation of Ca(2+) influx ranged over ∼20 mV. Ca(2+) influx at AZs facing away from the ganglion activated at weaker depolarizations. Estimates of AZ size and Ca(2+) channel number were correlated and larger when AZs faced the ganglion. Disruption of the deafness gene GIPC3 in mice shifted the activation of presynaptic Ca(2+) influx to more hyperpolarized potentials and increased the spontaneous SGN discharge. Moreover, Gipc3 disruption enhanced Ca(2+) influx and exocytosis in IHCs, reversed the spatial gradient of maximal Ca(2+) influx in IHCs, and increased the maximal firing rate of SGNs at sound onset. We propose that IHCs diversify Ca(2+) channel properties among AZs and thereby contribute to decomposing auditory information into complementary representations in SGNs.

Variable synaptic strengths controls the firing rate distribution in feedforward neural networks.

Heterogeneity of firing rate statistics is known to have severe consequences on neural coding. Recent experimental recordings in weakly electric fish indicate that the distribution-width of superficial pyramidal cell firing rates (trial- and time-averaged) in the electrosensory lateral line lobe (ELL) depends on the stimulus, and also that network inputs can mediate changes in the firing rate distribution across the population. We previously developed theoretical methods to understand how two attributes (synaptic and intrinsic heterogeneity) interact and alter the firing rate distribution in a population of integrate-and-fire neurons with random recurrent coupling. Inspired by our experimental data, we extend these theoretical results to a delayed feedforward spiking network that qualitatively capture the changes of firing rate heterogeneity observed in in-vivo recordings. We demonstrate how heterogeneous neural attributes alter firing rate heterogeneity, accounting for the effect with various sensory stimuli. The model predicts how the strength of the effective network connectivity is related to intrinsic heterogeneity in such delayed feedforward networks: the strength of the feedforward input is positively correlated with excitability (threshold value for spiking) when firing rate heterogeneity is low and is negatively correlated with excitability with high firing rate heterogeneity. We also show how our theory can be used to predict effective neural architecture. We demonstrate that neural attributes do not interact in a simple manner but rather in a complex stimulus-dependent fashion to control neural heterogeneity and discuss how it can ultimately shape population codes.

Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior.

Type IV ATPases are putative aminophospholipid translocases (APLTs), more commonly known as flippases. A pronounced induction of the flippase Atp8a1 was observed in post-mortem tissue homogenates from the hippocampus and temporal lobe of juvenile autistic subjects compared to age-matched controls. In order to simulate the human data, C57BL/6 mice were allowed to develop after intra-hippocampal injection of recombinant lentivirus expressing Atp8a1 at the early developmental stage of postnatal day 6 (P6). Transmission electron microscopy (TEM) analysis of the lentivirus-Atp8a1 treated (Atp8a1+) mice in adulthood revealed fewer and weaker excitatory synapses in the hippocampal CA1 region compared to mice injected with empty virus. Significant inhibition of the Schaffer collateral pathway was observed in the Atp8a1+ mice in paired-pulse recording (PPR) at 20-ms inter-stimulus interval. In the three-chambered sociability test, the Atp8a1+ mice displayed no preference for an encaged stranger mouse over a novel object, which is a characteristic autistic-like behavior. In sharp contrast, Atp8a1 (-/-) mice displayed a preference for a stranger mouse over the novel object, which is characteristic of neurotypical mouse behavior. However, similar to the Atp8a1+ mice, the Atp8a1 (-/-) mice harbored fewer and weaker excitatory synapses in CA1 compared to wild-type controls, and displayed inhibition at 20-ms inter-stimulus interval in PPR. These findings suggest that both elevated and diminished levels of Atp8a1 during early development are detrimental to brain connectivity, but only elevated Atp8a1 is associated with aberrant social behavior. Mice with augmented levels of Atp8a1 may therefore serve as a potential model in autism research.

Involvement of hippocampal inputs and intrinsic circuit in the acquisition of context and cues during classical conditioning in behaving rabbits.

Learning-related changes in strength in selected hippocampal synapses have been described recently. However, information is scarce regarding the spatial-temporal sequence of changes in synaptic weights taking place during the acquisition of a classical conditioning task and the contribution of both context (environmental details) and cues (conditioned and unconditioned stimuli: CS, US) to those activity-dependent changes. We recorded in rabbits the monosynaptic field excitatory postsynaptic potentials (fEPSPs) evoked at 6 different hippocampal synapses during the acquisition and extinction of a classical eyeblink conditioning using trace or delay paradigms, as well as during pseudoconditioning and in the absence of CS and US presentations (context). Context and pseudoconditioning training evoked early, lasting changes in synaptic strength in perforant pathway synapses in dentate gyrus (PP-DG), and hippocampal CA3 (PP-CA3) and CA1 (PP-CA1) areas. Pseudoconditioning also evoked early, nonlasting changes in strength within the intrinsic hippocampal circuit (CA3-CA1 and CA3-cCA1 synapses). In contrast, during both trace and delay training sessions, synaptic changes in strength were mostly noticed within the intrinsic hippocampal circuit (DG-CA3, CA3-CA1, CA3-cCA1). The response of hippocampal synapses to afferent impulses seems to be modulated by both context and cues during associative learning in behaving rabbits.

Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses.

Chronic stress is thought to impart risk for depression via alterations in brain structure and function, but contributions of specific mediators in generating these changes remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated changes in cognitive and affective behavioral tasks (spatial memory consolidation, anhedonia, and neohypophagia) with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) synapses, an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype characterized by reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptor-mediated excitation at TA-CA1 synapses, decreased AMPA-type glutamate receptor subunit 1 protein expression, and altered serotonin-1B receptor-mediated potentiation. Repeatedly blunting stress-induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress-sensitive synapses at key loci throughout corticomesolimbic reward circuitry appears critical for maintaining normal cognitive and emotional behavior.

Functional basis of associative learning and its relationships with long-term potentiation evoked in the involved neural circuits: Lessons from studies in behaving mammals.

While contemporary neuroscience is paying increasing attention to subcellular and molecular events and other intracellular phenomena underlying the acquisition, storage, and retrieval of newly acquired motor and cognitive abilities, parallel attention should be paid to the study of the electrophysiological phenomena taking place at selected cortical and subcortical neuronal and synaptic sites during the precise moment of learning acquisition, extinction, and recall. These in vivo approaches to the study of learning and memory processes will allow the proper integration of the important information collected from in vitro and delayed molecular studies. Here, we summarize studies in behaving mammals carried out in our laboratory during the past ten years on the relationships between experimentally evoked long-term potentiation (LTP) and activity-dependent changes in synaptic strength taking place in hippocampal, prefrontal and related cortical and subcortical circuits during the acquisition of classical eyeblink conditioning or operant learning tasks. These studies suggest that different hippocampal synapses are selectively modified in strength during the acquisition of classical, but not instrumental, learning tasks. In contrast, selected prefrontal and striatum synapses are more directly modified by operant conditioning. These studies also show that besides N-methyl-D-aspartate (NMDA) receptors, many other neurotransmitter, intracellular mediating, and transcription factors participate in these two types of associative learning. Although experimentally evoked LTP seems to prevent the acquisition of classical eyeblink conditioning when induced at selected hippocampal synapses, it proved to be ineffective in preventing the acquisition of operant conditioned tasks when induced at numerous hippocampal, prefrontal, and striatal sites. The differential roles of these cortical structures during these two types of associative learning are discussed, and a diagrammatic representation of their respective functions is presented.

Effects of TRPV1 on the hippocampal synaptic plasticity in the epileptic rat brain.

Temporal lobe epilepsy is often presented by medically intractable recurrent seizures due to dysfunction of temporal lobe structures, mostly the temporomesial structures. The role of transient receptor potential vaniloid 1 (TRPV1) activity on synaptic plasticity of the epileptic brain tissues was investigated. We studied hippocampal TRPV1 protein content and distribution in the hippocampus of epileptic rats. Furthermore, the effects of pharmacologic modulation of TRPV1 receptors on field excitatory postsynaptic potentials have been analyzed after induction of long term potentiation (LTP) in the hippocampal CA1 and CA3 areas after 1 day (acute phase) and 3 months (chronic phase) of pilocarpine-induced status epilepticus (SE). A higher expression of TRPV1 protein in the hippocampus as well as a higher distribution of this channel in CA1 and CA3 areas in both acute and chronic phases of pilocarpine-induced SE was observed. Activation of TRPV1 using capsaicin (1 µM) enhanced LTP induction in CA1 region in non-epileptic rats. Inhibition of TRPV1 by capsazepine (10 µM) did not affect LTP induction in non-epileptic rats. In acute phase of SE, activation of TRPV1 enhanced LTP in both CA1 and CA3 areas but TRPV1 inhibition did not affect LTP. In chronic phase of SE, application of TRPV1 antagonist enhanced LTP induction in CA1 and CA3 regions but TRPV1 activation had no effect on LTP. These findings indicate that a higher expression of TRPV1 in epileptic conditions is accompanied by a functional impact on the synaptic plasticity in the hippocampus. This suggests TRPV1 as a potential target in treatment of seizure attacks.

Synaptic excitation is regulated by the postsynaptic dSK channel at the Drosophila larval NMJ.

In the mammalian central nervous system, the postsynaptic small-conductance Ca(2+)-dependent K(+) (SK) channel has been shown to reduce postsynaptic depolarization and limit Ca(2+) influx through N-methyl-d-aspartate receptors. To examine further the role of the postsynaptic SK channel in synaptic transmission, we studied its action at the Drosophila larval neuromuscular junction (NMJ). Repetitive synaptic stimulation produced an increase in postsynaptic membrane conductance leading to depression of excitatory postsynaptic potential amplitude and hyperpolarization of the resting membrane potential (RMP). This reduction in synaptic excitation was due to the postsynaptic Drosophila SK (dSK) channel; synaptic depression, increased membrane conductance and RMP hyperpolarization were reduced in dSK mutants or after expressing a Ca(2+) buffer in the muscle. Ca(2+) entering at the postsynaptic membrane was sufficient to activate dSK channels based upon studies in which the muscle membrane was voltage clamped to prevent opening voltage-dependent Ca(2+) channels. Increasing external Ca(2+) produced an increase in resting membrane conductance and RMP that was not seen in dSK mutants or after adding the glutamate-receptor blocker philanthotoxin. Thus it appeared that dSK channels were also activated by spontaneous transmitter release and played a role in setting membrane conductance and RMP. In mammals, dephosphorylation by protein phosphatase 2A (PP2A) increased the Ca(2+) sensitivity of the SK channel; PP2A appeared to increase the sensitivity of the dSK channel since PP2A inhibitors reduced activation of the dSK channel by evoked synaptic activity or increased external Ca(2+). It is proposed that spontaneous and evoked transmitter release activate the postsynaptic dSK channel to limit synaptic excitation and stabilize synapses.

From synapse to sensation: the role of circTulp4.

Recent work by Giusti and colleagues showed that circTulp4 modulates excitatory synaptic strength. Knocking down circTulp4 disrupts the excitation-inhibition (E/I) balance in mice and leads to hypersensitivity toward aversive stimuli. These observations update our appreciation of the functions of circular (circ)RNA in the nervous system and their potential implication in neurodevelopmental and neuropsychiatric disorders.