Changes In Short-term Synaptic Plasticity Research Articles

Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in the Male and Female Hippocampus of a Rat Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus.

S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5

Alzheimer's disease (AD) is the most common form of dementia, which is neuropathologically characterized by extracellular senile plaques containing amyloid-β and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Previous studies have suggested a role for septin (SEPTIN) protein family members in AD-associated cellular processes. Here, we elucidated the potential role of presynaptic SEPTIN5 protein and its post-translational modifications in the molecular pathogenesis of AD. RNA and protein levels of SEPTIN5 showed a significant decrease in human temporal cortex in relation to the increasing degree of AD-related neurofibrillary pathology. Conversely, an increase in the phosphorylation of the functionally relevant SEPTIN5 phosphorylation site S327 was observed already in the early phases of AD-related neurofibrillary pathology, but not in the cerebrospinal fluid of individuals fulfilling the criteria for mild cognitive impairment due to AD. According to the mechanistic assessments, a link between SEPTIN5 S327 phosphorylation status and the effects of SEPTIN5 on amyloid precursor protein processing and markers of autophagy was discovered in mouse primary cortical neurons transduced with lentiviral constructs encoding wild type SEPTIN5 or SEPTIN5 phosphomutants (S327A and S327D). C57BL/6 J mice intrahippocampally injected with lentiviral wild type SEPTIN5 or phosphomutant constructs did not show changes in cognitive performance after five to six weeks from the start of injections. However, SEPTIN5 S327 phosphorylation status was linked to changes in short-term synaptic plasticity ex vivo at the CA3-CA1 synapse. Collectively, these data suggest that SEPTIN5 and its S327 phosphorylation status play a pivotal role in several cellular processes relevant for AD.

Comparing the Seizure-Induced Impairment of Short-Term Plasticity in Dorsal and Ventral Hippocampus in Kindled Mice

There are many differences among dorsal and ventral hippocampal neural circuits that affect the synaptic plasticity. In this study we compared the occurrence of short-term plasticity in the field excitatory post synaptic potentials (fEPSP) in dorsal and ventral hippocampal CA1 area following kindled seizures. Animals (male C57 B6/J mice, 12 weeks of age) were kindled by intraperitoneal injections of pentylenetetrazole (PTZ) and fEPSPs were recorded from dorsal and ventral hippocampal slices. Short-term plasticity was evaluated by measuring fEPSP-slope and fEPSP-area following paired-pulse stimulation delivered at three inter-pulse intervals (20, 80 and 160 ms). Obtained results showed that in control slices fEPSP-slope was greater in ventral- compared to dorsal hippocampus, but there was no difference in fEPSP-area among two regions. In hippocampal slices of kindled animals, fEPSP-slope was similar in dorsal and ventral regions, but fEPSP-area was greater in ventral- compared to dorsal hippocampus. In addition, fEPSP-area was greater in kindled compared to control group only in ventral hippocampus. PTZ kindled slices showed impaired short-term facilitation and the paired-pulse index was reduced only at dorsal hippocampal slices. Kindling had no significant effect on paired-pulse ratio in ventral hippocampal slices. Our findings indicated that the seizure occurrence affected the neural activity of hippocampus in a regional dependent manner. Although kindling increased fEPSP-area in ventral hippocampus, kindling-induced changes in short-term synaptic plasticity was significant only in dorsal hippocampal slices compared to control group. The difference in the responses of hippocampal dorsal and ventral poles has to be considered in the future researches.

Commentary: On the possible role of stimulation duration for after-effects of transcranial alternating current stimulation.

In their recent article, Struber et al. (2015) demonstrate that 1s application of transcranial alternating current stimulation (tACS) do not lead to any significant changes in the phase and amplitude of the electroencephalogram (EEG) signal. Therefore, they concluded that it is too short to induce synaptic plasticity. This is a very important observation that sheds light on possible underlying mechanisms of tACS. Although the results clearly show the absence of certain specific tACS-induced electrophysiological after-effects when applied only for 1s, some additional considerations need to be made in order to fully interpret these null results as well as probe the mechanism of tACS at shorter timescales. An important question is whether at these smaller time scales, the lack of prolonged entrainment during the post stimulation session necessarily reflect a lack of tACS efficacy. Alternatively, these results might also suggest that for 1s stimulation paradigms, we are simply looking at the wrong electrophysiological measure. At these smaller time scales, changes in measures such as spike rate adaptation (Fernandez et al., 2011; Kar and Krekelberg, 2014), spike time precision (Reato et al., 2010), neurovascular coupling (Zheng et al., 2011; Kar and Wright, 2014) are likely to be more relevant for behavioral aftereffects. The EEG signal typically comprises of synchronized oscillations across the superficial cortex (for review, see Buzsaki et al., 2012). Hence it might be more sensitive to changes in entrainment whereas much less sensitive to these subtle effects (which might also still be behaviorally relevant). However, some of these changes might indeed be a result of changes in short-term synaptic plasticity (which is a very broad term). It must however be noted that the aforementioned mechanisms could also be a direct result of network entrainment during tACS but lack entrainment related features in the EEG measured at the scalp in the post tACS session. One way to test this hypothesis further, would be to use the method introduced by Helfrich et al. (2014) to remove the tACS-induced artifacts for the 1s tACS period, and estimate changes in EEG during stimulation. This would be very informative to test whether tACS applied at the individual alpha frequency (IAF) for 1s could entrain the underlying cortex at all. Then we would be able to say whether the lack of effect is despite similar entrainment during tACS. The effects of tACS on the underlying cortex often depends on the presence of an experimental task that actively recruits the underlying brain area or otherwise, produces a specific brain state. For instance, Kar and Krekelberg (2014) demonstrated, that tACS induced changes in human motion discrimination performance is only present when tACS was paired with the visual motion stimulus. Ten Hertz tACS applied for 4s reduced the after-effects of motion adaptation and the effects scaled with how much adaptation there was to begin with. Similarly, Feurra et al. (2013) also demonstrated the state dependent effects of tACS on the motor cortex. Given this brain state dependency of the tACS induced effects, it remains unclear whether the lack of tACS-induced aftereffect reported in the study could be due to an absence of an appropriate brain state in the stimulated area. In this regard, it might be interesting to probe the brain areas while doing a relevant task. Choosing the stimulation intensity is also a key consideration during tACS studies (Groppa et al., 2010). However, it is crucial to consider the confounding aspects of tACS-induced phosphenes (Kar and Krekelberg, 2012) and tactile sensations (Feurra et al., 2011). I argue that lower stimulation amplitudes might not necessarily control for phosphenes and these low amplitudes might fail to induce the desired cortical effects (entrainment). First, the accuracy of the threshold values are highly depended on the sensitivity of the adaptive method used to estimate them. In addition, we can never rule out the effects of subthreshold retinal stimulation during tACS. Hence, it is important to consider other strategies to design control experiments to rule out general effects of tACS (phosphenes, tactile sensations, reduced/increased arousal etc.). Some recent studies have used brain laterization to test their hypotheses (Kar and Krekelberg, 2014). But, given the large current spread during tACS and asymmetries between the two hemispheres of the human brain, this is not always feasible. Therefore, control strategies remain a challenging issue for tACS experiments. The Struber et al. (2015) study provides a lead into the hypothesis that tACS mechanisms vary according to stimulation duration. This can be addressed in future experiments, where the stimulation duration can be varied as an independent variable to systematically map out its relationship with the boost in entrainment, changes in coherence and other short-term plasticity related changes.

Neurotransmitter release in motor nerve terminals of a mouse model of mild spinal muscular atrophy

Spinal muscular atrophy is a genetic disease which severity depends on the amount of SMN protein, the product of the genes SMN1 and SMN2. Symptomatology goes from severe neuromuscular impairment leading to early death in infants to slow progressing motor deficits during adulthood. Much of the knowledge about the pathophysiology of SMA comes from studies using genetically engineered animal models of the disease. Here we investigated one of the milder models, the homozygous A2G SMA mice, in which the level of the protein is restored to almost normal levels by the addition of a mutated transgene to the severe SMN-deficient background. We examined neuromuscular function and found that calcium-dependent neurotransmitter release was significantly decreased. In addition, the amplitude of spontaneous endplate potentials was decreased, the morphology of NMJ altered, and slight changes in short-term synaptic plasticity were found. In spite of these defects, excitation contraction coupling was well preserved, possibly due to the safety factor of this synapse. These data further support that the quasi-normal restoration of SMN levels in severe cases preserves neuromuscular function, even when neurotransmitter release is significantly decreased at motor nerve terminals. Nevertheless, this deficit could represent a greater risk of motor impairment during aging or after injuries.

Activity-Mediated AMPA Receptor Remodeling, Driven by Alternative Splicing in the Ligand-Binding Domain

SummaryThe AMPA-type glutamate receptor (AMPAR) subunit composition shapes synaptic transmission and varies throughout development and in response to different input patterns. Here, we show that chronic activity deprivation gives rise to synaptic AMPAR responses with enhanced fidelity. Extrasynaptic AMPARs exhibited changes in kinetics and pharmacology associated with splicing of the alternative flip/flop exons. AMPAR mRNA indeed exhibited reprogramming of the flip/flop exons for GluA1 and GluA2 subunits in response to activity, selectively in the CA1 subfield. However, the functional changes did not directly correlate with the mRNA expression profiles but result from altered assembly of GluA1/GluA2 subunit splice variants, uncovering an additional regulatory role for flip/flop splicing in excitatory signaling. Our results suggest that activity-dependent AMPAR remodeling underlies changes in short-term synaptic plasticity and provides a mechanism for neuronal homeostasis.

β3 integrin is dispensable for conditioned fear and Hebbian forms of plasticity in the hippocampus

Integrins play key roles in the developing and mature nervous system, from promoting neuronal process outgrowth to facilitating synaptic plasticity. Recently, in hippocampal pyramidal neurons, β3 integrin (ITGβ3) was shown to stabilise synaptic AMPA receptors (AMPARs) and to be required for homeostatic scaling of AMPARs elicited by chronic activity suppression. To probe the physiological function for ITGβ3-dependent processes in the brain, we examined whether the loss of ITGβ3 affected fear-related behaviours in mice. ITGβ3-knockout (KO) mice showed normal conditioned fear responses that were similar to those of control wild-type mice. However, anxiety-like behaviour appeared substantially compromised and could be reversed to control levels by lentivirus-mediated re-expression of ITGβ3 bilaterally in the ventral hippocampus. In hippocampal slices, the loss of ITGβ3 activity did not compromise hebbian forms of plasticity--neither acute pharmacological disruption of ITGβ3 ligand interactions nor genetic deletion of ITGβ3 altered long-term potentiation (LTP) or long-term depression (LTD). Moreover, we did not detect any changes in short-term synaptic plasticity upon loss of ITGβ3 activity. In contrast, acutely disrupting ITGβ1-ligand interactions or genetic deletion of ITGβ1 selectively interfered with LTP stabilisation whereas LTD remained unaltered. These findings indicate a lack of requirement for ITGβ3 in the two robust forms of hippocampal long-term synaptic plasticity, LTP and LTD, and suggest differential roles for ITGβ1 and ITGβ3 in supporting hippocampal circuit functions.

Developmental shift of short-term synaptic plasticity in cortical organotypic slices

Although short-term synaptic plasticity (STP) is ubiquitous in neocortical synapses its functional role in neural computations is not well understood. Critical to elucidating the function of STP will be to understand how STP itself changes with development and experience. Previous studies have reported developmental changes in STP using acute slices. It is not clear, however, to what extent the changes in STP are a function of local ontogenetic programs or the result of the many different sensory and experience-dependent changes that accompany development in vivo. To address this question we examined the in vitro development of STP in organotypic slices cultured for up to 4weeks. Paired recordings were performed in L5 pyramidal neurons at different stages of in vitro development. We observed a shift in STP in the form of a decrease in the paired-pulse ratio (PPR) (less depression) from the second to fourth week in vitro. This shift in STP was not accompanied by a change in initial excitatory postsynaptic potential (EPSP) amplitude. Fitting STP to a quantitative model indicated that the developmental shift is consistent with presynaptic changes. Importantly, despite the change in the PPR we did not observe changes in the time constant governing STP. Since these experiments were conducted in vitro our results indicate that the shift in STP does not depend on in vivo sensory experience. Although sensory experience may shape STP, we suggest that developmental shifts in STP are at least in part ontogenetically determined.

A novel learning rule for long-term plasticity of short-term synaptic plasticity enhances temporal processing

It is well established that short-term synaptic plasticity (STP) of neocortical synapses is itself plastic – e.g., the induction of LTP and LTD tend to shift STP towards short-term depression and facilitation, respectively. What has not been addressed theoretically or experimentally is whether STP is “learned”; that is, is STP regulated by specific learning rules that are in place to optimize the computations performed at synapses, or, are changes in STP essentially an epiphenomenon of long-term plasticity? Here we propose that STP is governed by specific learning rules that operate independently and in parallel of the associative learning rules governing baseline synaptic strength. We describe a learning rule for STP and, using simulations, demonstrate that it significantly enhances the discrimination of spatiotemporal stimuli. Additionally we generate a set of experimental predictions aimed at testing our hypothesis.

The contribution of calcium/calmodulin-dependent protein-kinase II (CaMKII) to short-term plasticity at the neuromuscular junction

Calcium/calmodulin-dependent protein-kinase II (CaMKII) is a ubiquitous intracellular enzyme, which is implicated in learning and memory mechanisms in the central nervous system, however its contribution to peripheral cholinergic neurotransmission is not well characterized. This study evaluated the impact of CaMKII on the function of frog neuromuscular synapse using electrophysiological recordings. Application of the selective CaMKII inhibitor KN-93 (5 μM) did not significantly alter the parameters of evoked and spontaneous quantal acetylcholine release under low-frequency stimulation (0.03 Hz). KN-93, on the other hand, produced pronounced changes in short-term synaptic plasticity: particularly, KN-93 inhibits the second component of paired-pulse facilitation (interpulse intervals of 100 ms and longer) and strengthens the depression of synaptic transmission under high-frequency stimulation (50 Hz). These results imply that CaMKII plays an important role in presynaptic functions at the frog neuromuscular junction, and potentiates quantal acetylcholine release under high-frequency activity.

Low level postnatal methylmercury exposure in vivo alters developmental forms of short-term synaptic plasticity in the visual cortex of rat

Methylmercury (MeHg) has been previously shown to affect neurotransmitter release. Short-term synaptic plasticity (STP) is primarily related to changes in the probability of neurotransmitter release. To determine if MeHg affects STP development, we examined STP forms in the visual cortex of rat following in vivo MeHg exposure. Neonatal rats received 0 (0.9% NaCl), 0.75 or 1.5 mg/kg/day MeHg subcutaneously for 15 or 30 days beginning on postnatal day 5, after which visual cortical slices were prepared for field potential recordings. In slices prepared from rats treated with vehicle, field excitatory postsynaptic potentials (fEPSPs) evoked by paired-pulse stimulation at 20–200 ms inter-stimulus intervals showed a depression (PPD) of the second fEPSP (fEPSP2). PPD was also seen in slices prepared from rats after 15 day treatment with 0.75 or 1.5 mg/kg/day MeHg. However, longer duration treatment (30 days) with either dose of MeHg resulted in paired-pulse facilitation (PPF) of fEPSP2 in the majority of slices examined. PPF remained observable in slices prepared from animals in which MeHg exposure had been terminated for 30 days after completion of the initial 30 day MeHg treatment, whereas slices from control animals still showed PPD. MeHg did not cause any frequency- or region-preferential effect on STP. Manipulations of [Ca 2+] e or application of the GABA A receptor antagonist bicuculline could alter the strength and polarity of MeHg-induced changes in STP. Thus, these data suggest that low level postnatal MeHg exposure interferes with the developmental transformation of STP in the visual cortex, which is a long-lasting effect.

GABA B receptor-mediated presynaptic inhibition of glycinergic transmission onto substantia gelatinosa neurons in the rat spinal cord

The GABA B receptor-mediated presynaptic inhibition of glycinergic transmission was studied from young rat substantia gelatinosa (SG) neurons using a conventional whole-cell patch clamp technique. Action potential-dependent glycinergic inhibitory postsynaptic currents (IPSCs) were recorded from SG neurons in the presence of 3 mM kynurenic acid and 10 μM SR95531. In these conditions, baclofen (30 μM), a selective GABA B receptor agonist, greatly reduced the amplitude of glycinergic IPSCs and increased the paired-pulse ratio. Such effects were completely blocked by 3 μM CGP55845, a selective GABA B receptor antagonist, indicating that the activation of presynaptic GABA B receptors decreases glycinergic synaptic transmission. Glycinergic IPSCs were largely dependent on Ca 2+ influxes passing through presynaptic N- and P/Q-type Ca 2+ channels, and these channels contributed equally to the baclofen-induced inhibition of glycinergic IPSCs. However, the baclofen-induced inhibition of glycinergic IPSCs was not affected by either 100 μM SQ22536, an adenylyl cyclase inhibitor, or 1 mM Ba 2+, a G-protein coupled inwardly rectifying K + channel blocker. During the train stimulation (10 pulses at 20 Hz), which caused a marked synaptic depression of glycinergic IPSCs, baclofen at a 30 μM concentration completely blocked glycinergic synaptic depression, but at a 3 μM concentration it largely preserved glycinergic synaptic depression. Such GABA B receptor-mediated dynamic changes in short-term synaptic plasticity of glycinergic transmission onto SG neurons might contribute to the central processing of sensory signals.

Synaptotagmin-2 Is Essential for Survival and Contributes to Ca2+Triggering of Neurotransmitter Release in Central and Neuromuscular Synapses

Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca2+ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5' end of the synaptotagmin-2 gene was replaced by lacZ. Using beta-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at approximately 3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2-deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca2+-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca2+ triggering of neurotransmitter release.

Activation of Ras in neurons modifies synaptic vesicle docking and release

We have recently demonstrated that constitutive activation of Ha-Ras in differentiated neurons induces structural remodeling of both axons and dendrites in a transgenic mouse model (referred as synRas mice). Here we show that this activation of neuronal Ras enhances docking of synaptic vesicles to active zones, thereby leading to an increase in the size of the readily releasable pool of vesicles, while the size of the total pool of synaptic vesicles remained unchanged. The morphological phenotype was associated with corresponding increases in the probability of glutamate release as revealed by changes in short-term synaptic plasticity. We, therefore, conclude that neuronal Ras activity contributes to the regulation of synaptic plasticity in adult mammalian brain at the presynaptic level.