A silent eligibility trace enables dopamine‐dependent synaptic plasticity for reinforcement learning in the mouse striatum

Dopamine‐dependent synaptic plasticity is a candidate mechanism for reinforcement learning. A silent eligibility trace – initiated by synaptic activity and transformed into synaptic strengthening by later action of dopamine – has been hypothesized to explain the retroactive effect of dopamine in reinforcing past behaviour. We tested this hypothesis by measuring time‐dependent modulation of synaptic plasticity by dopamine in adult mouse striatum, using whole‐cell recordings. Presynaptic activity followed by postsynaptic action potentials (pre–post) caused spike‐timing‐dependent long‐term depression in D1‐expressing neurons, but not in D2 neurons, and not if postsynaptic activity followed presynaptic activity. Subsequent experiments focused on D1 neurons. Applying a dopamine D1 receptor agonist during induction of pre–post plasticity caused long‐term potentiation. This long‐term potentiation was hidden by long‐term depression occurring concurrently and was unmasked when long‐term depression blocked an L‐type calcium channel antagonist. Long‐term potentiation was blocked by a Ca²⁺‐permeable AMPA receptor antagonist but not by an NMDA antagonist or an L‐type calcium channel antagonist. Pre–post stimulation caused transient elevation of rectification – a marker for expression of Ca²⁺‐permeable AMPA receptors – for 2–4‐s after stimulation. To test for an eligibility trace, dopamine was uncaged at specific time points before and after pre‐ and postsynaptic conjunction of activity. Dopamine caused potentiation selectively at synapses that were active 2‐s before dopamine release, but not at earlier or later times. Our results provide direct evidence for a silent eligibility trace in the synapses of striatal neurons. This dopamine‐timing‐dependent plasticity may play a central role in reinforcement learning.     

The small‐conductance calcium‐activated potassium channel is a key modulator of firing and long‐term depression in the dorsal striatum

The striatum is considered to be critical for the control of goal‐directed action, with the lateral dorsal striatum (latDS) being implicated in modulation of habits and the nucleus accumbens thought to represent a limbic–motor interface. Although medium spiny neurons from different striatal subregions exhibit many similar properties, differential firing and synaptic plasticity could contribute to the varied behavioral roles across subregions. Here, we examined the contribution of small‐conductance calcium‐activated potassium channels (SKs) to action potential generation and synaptic plasticity in adult rat latDS and nucleus accumbens shell (NAS) projection neurons in vitro. The SK‐selective antagonist apamin exerted a prominent effect on latDS firing, significantly decreasing the interspike interval. Furthermore, prolonged latDS depolarization increased the interspike interval and reduced firing, and this enhancement was reversed by apamin. In contrast, NAS neurons exhibited greater basal firing rates and less regulation of firing by SK inhibition and prolonged depolarization. LatDS neurons also had greater SK currents than NAS neurons under voltage‐clamp. Importantly, SK inhibition with apamin facilitated long‐term depression (LTD) induction in the latDS but not the NAS, without alterations in glutamate release. In addition, SK activation in the latDS prevented LTD induction. Greater SK function in the latDS than in the NAS was not secondary to differences in sodium or inwardly rectifying potassium channel function, and apamin enhancement of firing did not reflect indirect action through cholinergic interneurons. Thus, these data demonstrate that SKs are potent modulators of action potential generation and LTD in the dorsal striatum, and could represent a fundamental cellular mechanism through which habits are regulated.     

A novel form of presynaptic CaMKII-dependent short-term potentiation between Lymnaea neurons

Short‐term plasticity is thought to form the basis for working memory, the cellular mechanisms of which are the least understood in the nervous system. In this study, using in vitro reconstructed synapses between the identified Lymnaea neuron visceral dorsal 4 (VD4) and left pedal dorsal 1 (LPeD1), we demonstrate a novel form of short‐term potentiation (STP) which is ‘use’‐ but not time‐dependent, unlike most previously defined forms of short‐term synaptic plasticity. Using a triple‐cell configuration we demonstrate for the first time that a single presynaptic neuron can reliably potentiate both inhibitory and excitatory synapses. We further demonstrate that, unlike previously described forms of STP, the synaptic potentiation between Lymnaea neurons does not involve postsynaptic receptor sensitization or presynaptic residual calcium. Finally, we provide evidence that STP at the VD4–LPeD1 synapse requires presynaptic calcium/calmodulin dependent kinase II (CaMKII). Taken together, our study identifies a novel form of STP which may provide the basis for both short‐ and long‐term potentiation, in the absence of any protein synthesis‐dependent steps, and involve CaMKII activity exclusively in the presynaptic cell.     

Glutamate released spontaneously from astrocytes sets the threshold for synaptic plasticity

Astrocytes exhibit spontaneous calcium oscillations that could induce the release of glutamate as gliotransmitter in rat hippocampal slices. However, it is unknown whether this spontaneous release of astrocytic glutamate may contribute to determining the basal neurotransmitter release probability in central synapses. Using whole‐cell recordings and Ca²⁺ imaging, we investigated the effects of the spontaneous astrocytic activity on neurotransmission and synaptic plasticity at CA3–CA1 hippocampal synapses. We show here that the metabolic gliotoxin fluorocitrate (FC) reduces the amplitude of evoked excitatory postsynaptic currents and increases the paired‐pulse facilitation, mainly due to the reduction of the neurotransmitter release probability and the synaptic potency. FC also decreased intracellular Ca²⁺ signalling and Ca²⁺‐dependent glutamate release from astrocytes. The addition of glutamine rescued the effects of FC over the synaptic potency; however, the probability of neurotransmitter release remained diminished. The blockage of group I metabotropic glutamate receptors mimicked the effects of FC on the frequency of miniature synaptic responses. In the presence of FC, the Ca²⁺ chelator 1,2‐bis(2‐aminophenoxy)ethane‐N,N,N ′,N ′‐tetra‐acetate or group I metabotropic glutamate receptor antagonists, the excitatory postsynaptic current potentiation induced by the spike‐timing‐dependent plasticity protocol was blocked, and it was rescued by delivering a stronger spike‐timing‐dependent plasticity protocol. Taken together, these results suggest that spontaneous glutamate release from astrocytes contributes to setting the basal probability of neurotransmitter release via metabotropic glutamate receptor activation, which could be operating as a gain control mechanism that regulates the threshold of long‐term potentiation. Therefore, endogenous astrocyte activity provides a novel non‐neuronal mechanism that could be critical for transferring information in the central nervous system.     

Dendritic mechanisms controlling the threshold and timing requirement of synaptic plasticity

Active conductances located and operating on neuronal dendrites are expected to regulate synaptic integration and plasticity. We investigate how Kv4.2‐mediated A‐type K⁺ channels and Ca²⁺‐activated K⁺ channels are involved in the induction process of Hebbian‐type plasticity that requires correlated pre‐ and postsynaptic activities. In CA1 pyramidal neurons, robust long‐term potentiation (LTP) induced by a theta burst pairing protocol usually occurred within a narrow window during which incoming synaptic potentials coincided with postsynaptic depolarization. Elimination of dendritic A‐type K⁺ currents in Kv4.2^?/? mice, however, resulted in an expanded time window, making the induction of synaptic potentiation less dependent on the temporal relation of pre‐ and postsynaptic activity. For the other type of synaptic plasticity, long‐term depression, the threshold was significantly increased in Kv4.2^?/? mice. This shift in depression threshold was restored to normal when the appropriate amount of internal free calcium was chelated during induction. In concert with A‐type channels, Ca²⁺‐activated K⁺ channels also exerted a sliding effect on synaptic plasticity. Blocking these channels in Kv4.2^?/? mice resulted in an even larger potentiation while by contrast, the depression threshold was shifted further. In conclusion, dendritic A‐type and Ca²⁺‐activated K⁺ channels dually regulate the timing‐dependence and thresholds of synaptic plasticity in an additive way. © 2010 Wiley‐Liss, Inc.     

Long‐term depression of inhibitory synaptic transmission induced by spike‐timing dependent plasticity requires coactivation of endocannabinoid and muscarinic receptors

The precise timing of pre‐postsynaptic activity is vital for the induction of long‐term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP‐iLTD. The STDP‐iLTD requires a postsynaptic Ca²⁺ increase, a release of endocannabinoids (eCBs), the activation of type‐1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP‐iLTD is independent of the activation of nicotinic receptors, GABA_BRs and G protein‐coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP‐iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory

The cognitive role of melanin‐concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero‐lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long‐term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal‐dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long‐term potentiation and depression in the CA1 area of the hippocampus. Post‐tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre‐synaptic forms of short‐term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short‐term memory T‐maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short‐term memory by impairing short‐term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short‐term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.     

Fast‐spiking interneurons of the rat ventral striatum: temporal coordination of activity with principal cells and responsiveness to reward

Although previous in vitro studies revealed inhibitory synaptic connections of fast‐spiking interneurons to principal cells in the striatum, uncertainty remains about the nature of the behavioural events that correlate with changes in interneuron activity and about the temporal coordination of interneuron firing with spiking of principal cells under natural conditions. Using in vivo tetrode recordings from the ventral striatum in freely moving rats, fast‐spiking neurons were distinguished from putative medium‐sized spiny neurons on the basis of their spike waveforms and rates. Cross‐correlograms of fast‐spiking and putative medium‐sized spiny neuron firing patterns revealed a variety of temporal relationships, including peaks of concurrent firing and transient decrements in medium‐sized spiny neuron spiking around fast‐spiking unit activity. Notably, the onset of these decrements was mostly in advance of the fast‐spiking unit firing. Many of these temporal relationships were dependent on the sleep–wake state. Coordinated activity was also found amongst pairs of the same phenotype, both fast‐spiking units and putative medium‐sized spiny neurons, which was often marked by a broad peak of concurrent firing. When studying fast‐spiking neurons in a reward‐searching task, they generally showed a pre‐reward ramping increment in firing rate but a decrement specifically when the rat received reward. In conclusion, our data indicate that various forms of temporally coordinated activity exist amongst ventral striatal interneurons and principal cells, which cannot be explained by feed‐forward inhibitory circuits alone. Furthermore, firing patterns of ventral striatal fast‐spiking interneurons do not merely correlate with the general arousal state of the animal but display distinct reward‐related changes in firing rate.     

Matrix metalloprotease activity shapes the magnitude of EPSPs and spike plasticity within the hippocampal CA3 network

Matrix metalloproteases (MMP) play a pivotal role in long‐term synaptic plasticity, learning, and memory. The roles of different MMP subtypes are emerging, but the proteolytic activity of certain MMPs was shown to support these processes through the structural and functional modification of hippocampal Schaeffer collateral and mossy fiber (MF) synapses. However, certain patterns of synaptic activity are additionally associated with non‐synaptic changes, such as the scaling of neuronal excitability. However, the extent to which MMPs affect this process remains unknown. We determined whether MMP activity interferes with excitatory post‐synaptic potential EPSP‐to‐spike (E–S) coupling under conditions of varying synaptic activity. We evoked short‐ and long‐term synaptic plasticity at associational/commissural (A/C) synapses of CA3 pyramidal neurons and simultaneously recorded population spikes (PSs) and EPSPs in acute rat (P30–60) brain slices in the presence of various MMP inhibitors. We found that MMP inhibition significantly reduced E–S coupling and shortened the PS latency associated with 4× 100 Hz stimulation or paired burst activity of MF–CA3 and A/C synapses. Moreover, MMP inhibition interfered with the scaling of amplitude of measured signals during high‐frequency trains, thus affecting the induction of long‐term potentiation (LTP). The inhibition of L‐type voltage‐gated calcium channels with 20 µM nifedipine or GABA‐A receptors with 1–30 µM picrotoxin did not occlude the effects of MMP inhibitors. However, MMP inhibition significantly reduced the LTP of NMDA receptor‐mediated EPSPs. Finally, the analysis of LTP saturation with multiple single (1× 100 Hz) or packed (4× 100 Hz) trains indicated that MMPs support E–S coupling evoked by selected synaptic activity patterns and set the ceiling for tetanically evoked E–S LTP. In conclusion, the activity of MMPs, particularly MMP‐3, regulated the magnitude of EPSPs and spike plasticity in the CA3 network and may affect information processing. Our data provide a novel link between MMP activity and neural excitability. Therefore, by limiting the number of firing neurons, MMP may functionally act beyond the synapse. © 2013 Wiley Periodicals, Inc.     

Apamin induces plastic changes in hippocampal neurons in senile Sprague-Dawley rats

Apamin is a neurotoxin extracted from honey bee venom and is a selective blocker of small‐conductance Ca²⁺‐activated K⁺ channels (SK). Several behavioral and electrophysiological studies indicate that SK‐blockade by apamin may enhance neuron excitability, synaptic plasticity, and long‐term potentiation in the CA1 hippocampal region, and, for that reason, apamin has been proposed as a therapeutic agent in Alzheimer's disease treatment. However, the dendritic morphological mechanisms implied in such enhancement are unknown. In the present work, Golgi–Cox stain protocol and Sholl analysis were used to study the effect of apamin on the dendritic morphology of pyramidal neurons from hippocampus and the prefrontal cortex as well as on the medium spiny neurons from the nucleus accumbens and granule cells from the dentate gyrus (DG) of the hippocampus. We found that only granule cells from the DG and pyramidal neurons from dorsal and ventral hippocampus were altered in senile rats injected with apamin. Our research suggests that apamin may increase the dendritic morphology in the hippocampus, which could be related to the neuronal excitability and synaptic plasticity enhancement induced by apamin. Synapse 2011. © 2011 Wiley‐Liss, Inc.     

Hippocampal long-term depression is enhanced, depotentiation is inhibited and long-term potentiation is unaffected by the application of a selective c-Jun N-terminal kinase inhibitor to freely behaving rats

Synaptic plasticity is regarded as the major candidate mechanism for synaptic information storage and memory formation in the hippocampus. Mitogen‐activated protein kinases have recently emerged as an important regulatory factor in many forms of synaptic plasticity and memory. As one of the subfamilies of mitogen‐activated protein kinases, extracellular‐regulated kinase is involved in the in vitro induction of long‐term potentiation (LTP), whereas p38 mediates metabotropic glutamate receptor‐dependent long‐term depression (LTD) in vitro. Although c‐Jun N‐terminal kinase (JNK) has also been implicated in synaptic plasticity, the in vivo relevance of JNK activity to different forms of synaptic plasticity remains to be further explored. We investigated the effect of inhibition of JNK on different forms of synaptic plasticity in the dentate gyrus of freely behaving adult rats. Intracereboventricular application of c‐Jun N‐terminal protein kinase‐inhibiting peptide (D‐JNKI) (96 ng), a highly selective JNK inhibitor peptide, did not affect basal synaptic transmission but reduced neuronal excitability with a higher dose (192 ng). Application of D‐JNKI, at a concentration that did not affect basal synaptic transmission, resulted in reduced specific phosphorylation of the JNK substrates postsynaptic density 95kD protein (PSD 95) and c‐Jun, a significant enhancement of LTD and a facilitation of short‐term depression into LTD. Both LTP and short‐term potentiation were unaffected. An inhibition of depotentiation (recovery of LTP) occurred. These data suggest that suppression of JNK‐dependent signalling may serve to enhance synaptic depression, and indirectly promote LTP through impairment of depotentiation.     

Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: Role of M1 muscarinic receptors

Broad‐spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short‐ and long‐term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock‐in (Tor1a^+/Δgag) mice heterozygous for ΔE‐torsinA and their controls (Tor1a^+/+ mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M₁ antagonist, VU0255035. Tor1a^+/Δgag mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short‐term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long‐term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M₁‐preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M₁ receptors was further demonstrated by their ability to counteract the M₁‐dependent potentiation of N‐methyl‐d ‐aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M₁ muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder. © 2014 International Parkinson and Movement Disorder Society     

Intrinsic cellular and molecular properties of in vivo hippocampal synaptic plasticity are altered in the absence of key synaptic matrix molecules

Hippocampal synaptic plasticity comprises a key cellular mechanism for information storage. In the hippocampus, both long‐term potentiation (LTP) and long‐term depression (LTD) are triggered by synaptic Ca²⁺‐elevations that are typically mediated by the opening of voltage‐gated cation channels, such as N‐methyl‐d ‐aspartate receptors (NMDAR), in the postsynaptic density. The integrity of the post‐synaptic density is ensured by the extracellular matrix (ECM). Here, we explored whether synaptic plasticity is affected in adult behaving mice that lack the ECM proteins brevican, neurocan, tenascin‐C, and tenascin‐R (KO). We observed that the profiles of synaptic potentiation and depression in the dentate gyrus (DG) were profoundly altered compared to plasticity profiles in wild‐type littermates (WT). Specifically, synaptic depression was amplified in a frequency‐dependent manner and although late‐LTP (>24 hr) was expressed following strong afferent tetanization, the early component of LTP (<75 min post‐tetanization) was absent. LTP (>4 hr) elicited by weaker tetanization was equivalent in WT and KO animals. Furthermore, this latter form of LTP was NMDAR‐dependent in WT but not KO mice. Scrutiny of DG receptor expression revealed significantly lower levels of both the GluN2A and GluN2B subunits of the N‐methyl‐d ‐aspartate receptor, of the metabotropic glutamate receptor, mGlu5 and of the L‐type calcium channel, Ca_v1.3 in KO compared to WT animals. Homer 1a and of the P/Q‐type calcium channel, Ca_v1.2 were unchanged in KO mice. Taken together, findings suggest that in mice that lack multiple ECM proteins, synaptic plasticity is intact, but is fundamentally different.     

Interaction of inhibition and triplets of excitatory spikes modulates the NMDA‐R‐mediated synaptic plasticity in a computational model of spike timing‐dependent plasticity

Spike timing‐dependent plasticity (STDP) experiments have shown that a synapse is strengthened when a presynaptic spike precedes a postsynaptic one and depressed vice versa. The canonical form of STDP has been shown to have an asymmetric shape with the peak long‐term potentiation at +6 ms and the peak long‐term depression at ?5 ms. Experiments in hippocampal cultures with more complex stimuli such as triplets (one presynaptic spike combined with two postsynaptic spikes or one postsynaptic spike with two presynaptic spikes) have shown that pre–post–pre spike triplets result in no change in synaptic strength, whereas post–pre–post spike triplets lead to significant potentiation. The sign and magnitude of STDP have also been experimentally hypothesized to be modulated by inhibition. Recently, a computational study showed that the asymmetrical form of STDP in the CA1 pyramidal cell dendrite when two spikes interact switches to a symmetrical one in the presence of inhibition under certain conditions. In the present study, I investigate computationally how inhibition modulates STDP in the CA1 pyramidal neuron dendrite when it is driven by triplets. The model uses calcium as the postsynaptic signaling agent for STDP and is shown to be consistent with the experimental triplet observations in the absence of inhibition: simulated pre–post–pre spike triplets result in no change in synaptic strength, whereas simulated post–pre–post spike triplets lead to significant potentiation. When inhibition is bounded by the onset and offset of the triplet stimulation, then the strength of the synapse is decreased as the strength of inhibition increases. When inhibition arrives either few milliseconds before or at the onset of the last spike in the pre–post–pre triplet stimulation, then the synapse is potentiated. Variability in the frequency of inhibition (50 vs. 100 Hz) produces no change in synaptic strength. Finally, a 5% variation in model's calcium parameters (calcium thresholds) proves that the model's performance is robust. © 2012 Wiley Periodicals, Inc.     

Long‐lasting modulation of synaptic plasticity in rat hippocampus after early‐life complex febrile seizures

A small fraction of children with febrile seizures appears to develop cognitive impairments. Recent studies in a rat model of hyperthermia‐induced febrile seizures indicate that prolonged febrile seizures early in life have long‐lasting effects on the hippocampus and induce cognitive deficits. However, data on network plasticity and the nature of cognitive deficits are conflicting. We examined three specific measures of hippocampal plasticity in adult rats with a prior history of experimental febrile seizures: (i) activity‐dependent synaptic plasticity (long‐term potentiation and depression) by electrophysiological recordings of Schaffer collateral/commissural‐evoked field excitatory synaptic potentials in CA1 of acute hippocampal slices; (ii) Morris water maze spatial learning and memory; and (iii) hippocampal mossy fiber plasticity by Timm histochemistry and quantification of terminal sprouting in CA3 and the dentate gyrus. We found enhanced hippocampal CA1 long‐term potentiation and reduced long‐term depression but normal spatial learning and memory in adult rats that were subjected to experimental febrile seizures on postnatal day 10. Furthermore, rats with experimental febrile seizures showed modest but significant sprouting of mossy fiber collaterals into the inner molecular layer of the dentate gyrus in adulthood. We conclude that enhanced CA1 long‐term potentiation and mild mossy fiber sprouting occur after experimental febrile seizures, without affecting spatial learning and memory in the Morris water maze. These long‐term functional and structural alterations in hippocampal plasticity are likely to play a role in the enhanced seizure susceptibility in this model of prolonged human febrile seizures but do not correlate with overt cognitive deficits.     

Aberrant striatal plasticity is specifically associated with dyskinesia following levodopa treatment

Chronic levodopa treatment for Parkinson's disease often results in the development of abnormal involuntary movement, known as L ‐dopa‐induced dyskinesia (LIDs). Studies suggest that LIDs may be associated with aberrant corticostriatal plasticity. Using in vivo extracellular recordings from identified Type I and Type II medium spiny striatal neurons, chronic L ‐dopa treatment was found to produce abnormal corticostriatal information processing. Specifically, after chronic L ‐dopa treatment in dopamine‐depleted rats, there was a transition from a cortically evoked long‐term depression (LTD) to a complementary but opposing form of plasticity, long‐term potentiation, in Type II “indirect” pathway neurons. In contrast, LTD could still be induced in Type I neurons. Interestingly, the one parameter that correlated best with dyskinesias was the inability to de‐depress established LTD in Type I medium spiny striatal neurons. Taken as a whole, we propose that the induction of LIDs is due, at least in part, to an aberrant induction of plasticity within the Type II indirect pathway neurons combined with an inability to de‐depress established plastic responses in Type I neurons. Such information is critical for understanding the cellular mechanisms underlying one of the major caveats to L ‐dopa therapy. © 2010 Movement Disorder Society     

Long‐term plasticity of glutamatergic input from the subthalamic nucleus to the entopeduncular nucleus

The hyperdirect pathway of the basal ganglia bypasses the striatum, and delivers cortical information directly to the subthalamic nucleus (STN). In rodents, the STN excites the two output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and the substantia nigra reticulata (SNr). Thus, during hyperdirect pathway activation, the STN drives EP firing inhibiting the thalamus. We hypothesized that STN activity could induce long‐term changes to the STN‐>EP synapse. To test this hypothesis, we recorded in the whole‐cell mode from neurons in the EP in acute brain slices from rats while electrically stimulating the STN. Repetitive pre‐synaptic stimulation generated modest long‐term depression (LTD) in the STN‐>EP synapse. However, pairing EP firing with STN stimulation generated robust LTD that manifested for pre‐before post‐as well as for post‐ before pre‐synaptic pairing. This LTD was highly sensitive to the time difference and was not detected at a time delay of 10 ms. To investigate whether post‐synaptic calcium levels were important for LTD induction, we made dendritic recordings from EP neurons that revealed action potential back‐propagation and dendritic calcium transients. Buffering the dendritic calcium concentration in the EP neurons with EGTA generated long term potentiation instead of LTD. Finally, mild LTD could be induced by post‐synaptic activity alone that was blocked by an endocannabinoid 1 (CB1) receptor blocker. These results thus suggest there may be an adaptive mechanism for buffering the impact of the hyperdirect pathway on basal ganglia output which could contribute to the de‐correlation of STN and EP firing.     

Heterosynaptic long‐term depression mediated by ATP released from astrocytes

Heterosynaptic long‐term depression (hLTD) at untetanized synapses accompanying the induction of long‐term potentiation (LTP) spatially sharpens the activity‐induced synaptic potentiation; however, the underlying mechanism remains unclear. We found that hLTD in the hippocampal CA1 region is caused by stimulation‐induced ATP release from astrocytes that suppresses transmitter release from untetanized synaptic terminals via activation of P2Y receptors. Selective stimulation of astrocytes expressing channelrhodopsin‐2, a light‐gated cation channel permeable to Ca²⁺, resulted in LTD of synapses on neighboring neurons. This synaptic modification required Ca²⁺ elevation in astrocytes and activation of P2Y receptors, but not N‐methyl‐D ‐aspartate receptors. Furthermore, blocking P2Y receptors or buffering astrocyte intracellular Ca²⁺ at a low level prevented hLTD without affecting LTP induced by SC stimulation. Thus, astrocyte activation is both necessary and sufficient for mediating hLTD accompanying LTP induction, strongly supporting the notion that astrocytes actively participate in activity‐dependent synaptic plasticity of neural circuits. © 2012 Wiley Periodicals, Inc.     

Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity

α‐Thalassemia X‐linked intellectual disability (ATR‐X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2‐type chromatin‐remodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX‐cKO) causes deficits in long‐term hippocampus‐dependent spatial memory. Thus, we hypothesized that ATRX‐cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane‐anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired‐pulse facilitation (PPF) at 50‐ms interpulse interval, and by their long‐term potentiation (LTP) induced by theta‐frequency burst stimulation. Baseline single‐pulse excitatory response at each synapse did not differ between ATRX‐cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX‐cKO mice. While basal dendritic LTP of the first‐pulse excitatory response was not affected in ATRX‐cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long‐term spatial memory deficits in ATRX‐cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR‐X syndrome patients.     

Diverse impact of neuronal activity at θ frequency on hippocampal long‐term plasticity

Brain oscillatory activity is considered an essential aspect of brain function, and its frequency can vary from <1 Hz to >200 Hz, depending on the brain states and projection. Episodes of rhythmic activity accompany hippocampus‐dependent learning and memory in vivo. Therefore, long‐term synaptic potentiation (LTP) and long‐term depression, which are considered viable substrates of learning and memory, are often experimentally studied in paradigms of patterned high‐frequency (>50 Hz) and low‐frequency (<5 Hz) stimulation. However, the impact of intermediate frequencies on neuronal plasticity remains less well understood. In particular, hippocampal neurons are specifically tuned for activity at θ frequency (4–8 Hz); this band contributes significantly to electroencephalographic signals, and it is likely to be involved in shaping synaptic strength in hippocampal circuits. Here, we review in vitro and in vivo studies showing that variation of θ‐activity duration may affect long‐term modification of synaptic strength and neuronal excitability in the hippocampus. Such θ‐pulse‐induced neuronal plasticity 1) is long‐lasting, 2) may be built on previously stabilized potentiation in the synapse, 3) may produce opposite changes in synaptic strength, and 4) requires complex molecular machinery. Apparently innocuous episodes of low‐frequency synaptic activity may have a profound impact on network signaling, thereby contributing to information processing in the hippocampus and beyond. In addition, θ‐pulse‐induced LTP might be an advantageous protocol in studies of specific molecular mechanisms of synaptic plasticity. © 2015 Wiley Periodicals, Inc.