Age-dependent alterations of long-term synaptic plasticity in thyroid-deficient rats

Thyroid hormone deficiency during a critical period of development profoundly affects cognitive functions such as attention, learning, and memory, but the synaptic alterations underlying these deficits remain unexplored. The present study examines the effect of congenital hypothyroidism on long-term synaptic plasticity. This plasticity is believed to be essential for learning and memory and for activity-dependent regulation of synapse formation in the developing brain. We found that the neonatal expression of long-term potentiation (LTP), long-term depression (LTD), depotentiation, and de-depression in hippocampal slices from hypothyroid animals was similar to that of controls. To examine the postnatal development of these plasticities, we used slices from neonatal (2-3 weeks) and adult (7-8 weeks) rats. This work demonstrates that the ability to express all these forms of synaptic plasticity is reduced in an age-dependent manner in control rats. LTP and depotentiation are also downregulated in adult hypothyroid rats, but we have found that de-depression is not affected during maturation. In addition, these animals express LTD at ages at which controls fail to induce it. In contrast, input/output experiments have shown greater levels of basal synaptic efficacy in hypothyroid adults, and this effect is probably related to the higher probability of release observed by paired-pulse experiments. Nevertheless, these effects appear to be unrelated to the differences observed in long-term synaptic plasticity, as no correlation was found between basal synaptic efficacy and the degree of LTD and de-depression. Furthermore, the NMDA-receptor antagonist amino-phosphonopentanoic acid (APV) completely blocked LTD, which suggests a postsynaptic locus of this alteration. Because LTD has been associated with novelty acquisition, we suggest that the greater LTD observed in adult hypothyroid rats might be related to the hyperactivity of these animals. However, other possibilities such as a retarded maturation of synaptic plasticity must be taken into account.     

Ethanol reverses the direction of long-term synaptic plasticity in the dorsomedial striatum

The striatum is a critical structure for the control of voluntary behaviour, and striatal synaptic plasticity has been implicated in instrumental learning. As ethanol consumption can cause impairments in cognition, learning, and action selection, it is important to understand the effects of this drug on striatal function. In this study we examined the effects of ethanol on long-term synaptic plasticity in the dorsomedial striatum (DMS), a striatal subregion that plays a central role in the acquisition and selection of goal-directed actions. Ethanol was found to impair N-methyl-d-aspartic acid receptor (NMDAR)-dependent long-term potentiation (LTP) dose-dependently in the DMS, and to promote long-term depression (LTD) at the highest concentration (50 mm) used. These results suggest that ethanol, at a concentration usually associated with mild intoxication, could significantly change experience-dependent modification of corticostriatal circuits underlying the learning of goal-directed instrumental actions.     

Differential roles of basolateral and central amygdala on the effects of uncontrollable stress on hippocampal synaptic plasticity

The amygdala is considered central in mediating stress-related changes of hippocampal functions. However, it remains unclear whether different amygdala subnuclei have different roles in coordinating stress effects. Here, we report that stress exposure caused an immediate increase of extracellular signal-regulated kinase (ERK)1/2 phosphorylation in the hippocampal area CA1 and the basolateral amygdala (BLA) and after a delay in the central amygdala (CEA). Exposure to the novel environment following stress increased ERK1/2 phosphorylation in the CEA, but reversed the stress-induced increase of ERK1/2 phosphorylation in the hippocampal area CA1 and the BLA. Either ERK1/2 inhibitor U0126 or N-methyl-D-aspartate (NMDA) receptor antagonist DL-(-)-2-amino-5-phosphonopentanoic acid (APV) administration into the BLA, but not the CEA, blocked the stress effects on hippocampal long-term potentiation (LTP) and long-term depression. Novelty-exploration-induced reversal of stress effects was prevented when animals were injected U0126 or APV into the CEA, but not the BLA, before subjected to the novel environment. The ability of novelty exploration to reverse the stress effects was mimicked by intra-CEA infusion of NMDA. These findings suggest that BLA ERK1/2 signaling pathway is critical to mediate the stress effects on hippocampal synaptic plasticity; the activation of CEA ERK1/2, in contrast, appears to mediate the reversal of stress effects.     

A putative lysophosphatidylinositol receptor GPR55 modulates hippocampal synaptic plasticity

GPR55, an orphan G‐protein coupled receptor, is activated by lysophosphatidylinositol (LPI) and the endocannabinoid anandamide, as well as by other compounds including THC. LPI is a potent endogenous ligand of GPR55 and neither GPR55 nor LPIs' functions in the brain are well understood. While endocannabinoids are well known to modulate brain synaptic plasticity, the potential role LPI could have on brain plasticity has never been demonstrated. Therefore, we examined not only GPR55 expression, but also the role its endogenous ligand could play in long‐term potentiation, a common form of synaptic plasticity. Using quantitative RT‐PCR, electrophysiology, and behavioral assays, we examined hippocampal GPR55 expression and function. qRT‐PCR results indicate that GPR55 is expressed in hippocampi of both rats and mice. Immunohistochemistry and single cell PCR demonstrates GPR55 protein in pyramidal cells of CA1 and CA3 layers in the hippocampus. Application of the GPR55 endogenous agonist LPI to hippocampal slices of GPR55^+/+ mice significantly enhanced CA1 LTP. This effect was absent in GPR55^?/? mice, and blocked by the GPR55 antagonist CID 16020046. We also examined paired‐pulse ratios of GPR55^?/? and GPR55^+/+ mice with or without LPI and noted significant enhancement in paired‐pulse ratios by LPI in GPR55^+/+ mice. Behaviorally, GPR55^?/? and GPR55^+/+ mice did not differ in memory tasks including novel object recognition, radial arm maze, or Morris water maze. However, performance on radial arm maze and elevated plus maze task suggests GPR55^?/? mice have a higher frequency of immobile behavior. This is the first demonstration of LPI involvement in hippocampal synaptic plasticity.     

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.     

Prenatal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring

Clinical studies demonstrate that prenatal stress causes cognitive deficits and increases vulnerability to affective disorders in children and adolescents. The underlying mechanisms are not yet fully understood. Here, we reported that prenatal stress (10 unpredictable, 1 s, 0.8 mA foot shocks per day during gestational days 13-19) impaired long-term potentiation (LTP) but facilitated long-term depression (LTD) in hippocampal CA1 region in slices of the prenatal stressed offspring (5 weeks old). Cross-fostering neonate offspring by the prenatal stressed or control mothers did not change the effects of prenatal stress on the hippocampal LTP and LTD. Furthermore, prenatal stress enhanced the effects of acute stress on the hippocampal LTP and LTD and impaired spatial learning and memory in the Morris water maze in the young rat offspring. Therefore, prenatal stress alters synaptic plasticity and enhances the effects of acute stress on synaptic plasticity in the hippocampus, which may be the mechanism for the impaired spatial learning and memory in young rat offspring.     

Dysfunctional and compensatory synaptic plasticity in Parkinson's disease

In Parkinson's disease, a loss of dopamine neurons causes severe motor impairments. These motor impairments have long been thought to result exclusively from immediate effects of dopamine loss on neuronal firing in basal ganglia, causing imbalances of basal ganglia pathways. However, motor impairments and pathway imbalances may also result from dysfunctional synaptic plasticity – a novel concept of how Parkinsonian symptoms evolve. Here we built a neuro‐computational model that allows us to simulate the effects of dopamine loss on synaptic plasticity in basal ganglia. Our simulations confirm that dysfunctional synaptic plasticity can indeed explain the emergence of both motor impairments and pathway imbalances in Parkinson's disease, thus corroborating the novel concept. By predicting that dysfunctional plasticity results not only in reduced activation of desired responses, but also in their active inhibition, our simulations provide novel testable predictions. When simulating dopamine replacement therapy (which is a standard treatment in clinical practice), we observe a new balance of pathway outputs, rather than a simple restoration of non‐Parkinsonian states. In addition, high doses of replacement are shown to result in overshooting motor activity, in line with empirical evidence. Finally, our simulations provide an explanation for the intensely debated paradox that focused basal ganglia lesions alleviate Parkinsonian symptoms, but do not impair performance in healthy animals. Overall, our simulations suggest that the effects of dopamine loss on synaptic plasticity play an essential role in the development of Parkinsonian symptoms, thus arguing for a re‐conceptualisation of Parkinsonian pathophysiology.     

Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CA1 area in vivo

Repeated vivid recalls or flashbacks of traumatic memories and memory deficits are the cardinal features of post-traumatic stress disorder (PTSD). The underlying mechanisms are not fully understood yet. Here, we examined the effects of very strong fear conditioning (20 pairings of a light with a 1.5-mA, 0.5-s foot shock) and subsequent reexposure to the conditioning context (chamber A), a similar context (chamber B), and/or to the fear conditioned stimulus (CS) (a light) on synaptic plasticity in the hippocampal CA1 area in anesthetized Sprague-Dawley rats. The conditioning procedure resulted in very strong conditioned fear, as reflected by high levels of persistent freezing, to both the contexts and to the CS, 24 h after fear conditioning. The induction of long-term potentiation (LTP) was blocked immediately after fear conditioning. It was still markedly impaired 24 h after fear conditioning; reexposure to the conditioning chamber A (CA) or to a similar chamber B (CB) did not affect the impairment. However, presentation of the CS in the CA exacerbated the impairment of LTP, whereas the CS presentation in a CB ameliorated the impairment so that LTP induction did not differ from that of control groups. The induction of long-term depression (LTD) was facilitated immediately, but not 24 h, after fear conditioning. Only reexposure to the CS in the CA, but not reexposure to either chamber A or B alone, or the CS in chamber B, 24 h after conditioning, reinstated the facilitation of LTD induction. These data demonstrate that unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm can have profound effects on hippocampal synaptic plasticity, which may aid to understand the mechanisms underlying impairments of hippocampus-dependent memory by stress or in PTSD.     

Models of brain injury and alterations in synaptic plasticity

Animal models are crucial for understanding human pathophysiological processes and for understanding how connections are injured, lost, or even regenerated and/or repaired. When animal models are used in conjunction with theoretical computational models, an ideal combination is achieved that potentially yields insight and encourages the formation of new theories concerning connectionism, cognitive functioning, and synaptic mechanisms. Mechanisms regulating glutamate receptor activation and intracellular calcium levels are important for normal synaptic transmission. These mechanisms (and others) are also critical during and after brain injury when the potential exists for these mechanisms to function pathologically. Interestingly enough, the regulation of glutamate receptor activation and intracellular calcium levels is also involved in normal processes of neuronal and synaptic plasticity. In addition, studies have shown that neurotrophins and cytokines, which are released after brain injury, can be neuroprotective and may also be important in synaptic plasticity. Furthermore, synaptic plasticity is a phenomenon thought by many to be necessary for memory encoding. If this is the case, then research described in this review has significant scientific merit concerning plasticity and memory and clinical benefit for understanding pathophysiologic processes associated with brain injury and memory impairment. This paper reviews the application of experimental animal models of brain injury for simulating conditions of stroke, trauma, and epilepsy (and/or seizure generation) and the associated cellular mechanisms of brain injury. The paper also briefly addresses the advantage of using computational models in combination with experimental models for hypothesis building and for aiding in the interpretation of empirical data. Finally, it reviews studies concerning brain injury and synaptic plasticity.     

Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation

Aging is associated with an impaired ability to maintain long-term potentiation (LTP), but the underlying cause of the impairment remains unclear. To gain a better understanding of the cellular and molecular mechanisms responsible for this impairment, the synaptic transmission and plasticity were studied in the CA1 region of hippocampal slices from adult (6-8 months) and poor-memory (PM)-aged (23-24 months) rats. The one-way inhibitory avoidance learning task was used as the behavioral paradigm to screen PM-aged rats. With intracellular recordings, CA1 neurons of PM-aged rats exhibited a more hyperpolarized resting membrane potential, reduced input resistance, and increased amplitude of afterhyperpolarization and spike threshold, compared with those in adult rats. Although a reduction in the size of excitatory synaptic response was observed in PM-aged rats, no obvious differences were found between adult and PM-aged rats in the pharmacological properties of excitatory synaptic response, paired-pulse facilitation, or frequency-dependent facilitation, which was tested with trains of 10 pulses at 1, 5, and 10 Hz. Slices from the PM-aged rats displayed significantly reduced early-phase long-term potentiation (E-LTP) and late-phase LTP (L-LTP), and the entire frequency-response curve of LTP and LTD is modified to favor LTD induction. The susceptibility of time-dependent reversal of LTP by low-frequency afferent stimulation was also facilitated in PM-aged rats. Bath application of the protein phosphatase inhibitor, calyculin A, enhanced synaptic response in slices from PM-aged, but not adult, rats. In contrast, application of the cAMP-dependent protein kinase inhibitors, Rp-8-CPT-cAMPS and KT5720, induced a decrease in synaptic transmission only in slices from the adult rats. Furthermore, the selective beta-adrenergic receptor agonist, isoproterenol, and pertussis toxin-sensitive G-protein inhibitor, N-ethylmaleimide, effectively restored the deficit in E-LTP and L-LTP of PM-aged rats. These results demonstrate that age-related impairments of synaptic transmission and LTP may result from alterations in the balance of protein kinase/phosphatase activities.     

Different synaptic stimulation patterns influence the local androgenic and estrogenic neurosteroid availability triggering hippocampal synaptic plasticity in the male rat

Electrophysiological recordings were used to investigate the role of the local synthesis of 17β‐estradiol (E2) and 5α‐dihydrotestosterone (DHT) on synaptic long‐term effects induced in the hippocampal CA1 region of male rat slices. Long‐term depression (LTD) and long‐term potentiation (LTP), induced by different stimulation patterns, were examined under the block of the DHT synthesis by finasteride (FIN), and the E2 synthesis by letrozole (LET). We used low frequency stimulation (LFS) for LTD, high frequency stimulation (HFS) for LTP, and intermediate patterns differing in duration or frequency. We found that FIN reverted the LFS‐LTD into LTP and enhanced LTP induced by intermediate and HFSs. These effects were abolished by exogenous DHT at concentration higher than the basal one, suggesting a stimulus dependent increase in DHT availability. No effect on the synaptic responses was observed giving DHT alone. Moreover, we found that the inhibition of E2 synthesis influenced the HFS‐LTP by reducing its amplitude, and the exogenous E2 either enhanced HFS‐LTP or reverted the LFS‐LTD into LTP. The equivalence of the E2 concentration for rescuing the full HFS‐LTP under LET and reverting the LFS‐LTD into LTP suggests an enhancement of the endogenous E2 availability that is specifically driven by the HFS. No effect of FIN or LET was observed on the responses to stimuli that did not induce either LTD or LTP. This study provides evidence that the E2 and DHT availability combined with specific stimulation patterns is determinant for the sign and amplitude of the long‐term effects.     

Dynamic range of GSK3α not GSK3β is essential for bidirectional synaptic plasticity at hippocampal CA3‐CA1 synapses

Glycogen synthase kinase‐3 (GSK3), particularly the isoform GSK3β, has been implicated in a wide range of physiological systems and neurological disorders including Alzheimer's Disease. However, the functional importance of GSK3α has been largely untested. The multifunctionality of GSK3 limits its potential as a drug target because of inevitable side effects. Due to its greater expression in the CNS, GSK3β rather than GSK3α has also been assumed to be of primary importance in synaptic plasticity. Here, we investigate bidirectional long‐term synaptic plasticity in knockin mice with a point mutation in GSK3α or GSK3β that prevents their inhibitory regulation. We report that only the mutation in GSK3α affects long‐term potentiation (LTP) and depression (LTD). This stresses the importance of investigating isoform specificity for GSK3 in all systems and suggests that GSK3α should be investigated as a drug target in cognitive disorders including Alzheimer's Disease. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Chronic in vivo optogenetic stimulation modulates neuronal excitability,spine morphology,and Hebbian plasticity in the mouse hippocampus

Prolonged increases in excitation can trigger cell‐wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes, and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 hr of stimulation with 15‐ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin‐2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2‐expressing mice immediately after the end of stimulation. Finally, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.     

The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits,biochemical changes,and hippocampal synaptic plasticity in an animal model of depression

Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression‐associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression‐associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression‐induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long‐term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight‐arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression‐associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments. © 2014 Wiley Periodicals, Inc.     

GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity

Hippocampal rhythms in clock gene expression, enzymatic activity, and long‐term potentiation (LTP) are thought to underlie day–night differences in memory acquisition and recall. Glycogen synthase kinase 3‐beta (GSK3β) is a known regulator of hippocampal function, and inhibitory phosphorylation of GSK3β exhibits region‐specific differences over the light‐dark cycle. Here, we sought to determine whether phosphorylation of both GSK3α and GSK3β isoforms has an endogenous circadian rhythm in specific areas of the hippocampus and whether chronic inhibition or activation alters the molecular clock and hippocampal plasticity (LTP). Results indicated a significant endogenous circadian rhythm in phosphorylation of GSK3β, but not GSK3α, in hippocampal CA1 extracts from mice housed in constant darkness for at least 2 weeks. To examine the importance of this rhythm, genetic and pharmacological strategies were used to disrupt the GSK3 activity rhythm by chronically activating or inhibiting GSK3. Chronic activation of both GSK3 isoforms in transgenic mice (GSK3‐KI mice) diminished rhythmic BMAL1 expression. On the other hand, chronic treatment with a GSK3 inhibitor significantly shortened the molecular clock period of organotypic hippocampal PER2::LUC cultures. While WT mice exhibited higher LTP magnitude at night compared to day, the day–night difference in LTP magnitude remained with greater magnitude at both times of day in mice with chronic GSK3 activity. On the other hand, pharmacological GSK3 inhibition impaired day–night differences in LTP by blocking LTP selectively at night. Taken together, these results support the model that circadian rhythmicity of hippocampal GSK3β activation state regulates day/night differences in molecular clock periodicity and a major form of synaptic plasticity (LTP).     

Maternal care received by individual pups correlates with adult CA1 dendritic morphology and synaptic plasticity in a sex-dependent manner

Maternal care is an important environmental factor for rats early in life. Adult offspring from dams exhibiting extremely high versus low maternal care differ remarkably in dendritic complexity and long-term synaptic potentiation in the CA1 area. However, >70% of the pups do not belong to these extreme categories of maternal care, questioning the general relevance of these observations. Therefore, the present study investigated whether the influence of maternal care is discernable over its entire range and can serve as an index predicting later CA1 structure and function. The amount of licking and grooming (%LG) received was determined for each pup during the first postnatal week. In males, both total apical branch length and dendritic complexity correlated significantly and positively with %LG. In females, we observed a nonsignificant negative correlation, also when controlled for variations in oestradiol and progesterone levels. The correlation in females was significantly different from that in males. No significant correlation was observed between the %LG and the amount of synaptic potentiation, either in male or in female offspring, regardless of whether slices had been treated with corticosterone or vehicle. However, in male rats, the degree of potentiation seen after corticosterone compared to vehicle treatment was almost significantly related to the %LG received early in life; this differed significantly from that observed in females. The data from the present study suggest that %LG received early in life results in mild, yet sex-dependent effects on adult CA1 structure and function.     

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.     

The effects of intra‐hippocampal L‐thyroxine infusion on long‐term potentiation and long‐term depression: A possible role for the αvβ3 integrin receptor

Although the effects of long‐term experimental dysthyroidism on long‐term potentiation (LTP) and long‐term depression (LTD) have been documented, the relationship between LTP/LTD and acute administration of L‐thyroxine (T4) has not been described. Here, we investigated the effects of intra‐hippocampal administration of T4 on synaptic plasticity in the dentate gyrus of the hippocampal formation. After a 15‐minute baseline recording, LTP and LTD were induced by application of high‐ and low‐frequency stimulation protocols, respectively. Infusions of saline or T4 and tetraiodothyroacetic acid (tetrac), a T4 analog that inhibits binding of iodothyronines to the integrin αvβ3 receptor, either alone or together, were made during the stimulation protocols. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes, between 55 to 60 minutes, were used as a measure of the LTP/LTD magnitude and were analyzed by two‐way univariate ANOVA with T4 and tetrac as between‐subjects factors. The input–output curves of the infusion groups were comparable to each other, as shown by the non significant interaction observed between stimulus intensity and infused drug. The magnitude of the LTP in T4‐infused rats was significantly lower as compared to saline‐infused rats. Both the PS amplitude and the EPSP slope were depressed more markedly with T4 infusion than with saline, tetrac, and T4 + tetrac infusion. Data of this study provide in vivo evidence that T4 can promote LTD over LTP via the integrin αvβ3 receptor, and that the effect of endogenous T4 on this receptor can be suppressed by tetrac in the hippocampus. © 2016 Wiley Periodicals, Inc.