Plastic and behavioral abnormalities in experimental Huntington's disease: a crucial role for cholinergic interneurons

Huntington's disease (HD) is a fatal hereditary neurodegenerative disease causing degeneration of striatal spiny neurons, whereas cholinergic interneurons are spared. This cell-type specific pathology produces an array of abnormalities including involuntary movements, cognitive impairments, and psychiatric disorders. Although the genetic mutation responsible for HD has been identified, little is known about the early synaptic changes occurring within the striatal circuitry at the onset of clinical symptoms. We therefore studied the synaptic plasticity of spiny neurons and cholinergic interneurons in two animal models of early HD. As a pathogenetic model, we used the chronic subcutaneous infusion of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. This treatment caused striatal damage and impaired response flexibility in the cross-maze task as well as defective extinction of conditioned fear suggesting a perseverative behavior. In these animals, we observed a loss of depotentiation in striatal spiny neurons and a lack of long-term potentiation (LTP) in cholinergic interneurons. These abnormalities of striatal synaptic plasticity were also observed in R6/2 transgenic mice, a genetic model of HD, indicating that both genetic and phenotypic models of HD show cell-type specific alterations of LTP. We also found that in control rats, as well as in wild-type (WT) mice, depotentiation of spiny neurons was blocked by either scopolamine or hemicholinium, indicating that reversal of LTP requires activation of muscarinic receptors by endogenous acetylcholine. Our findings suggest that the defective plasticity of cholinergic interneurons could be the primary event mediating abnormal functioning of striatal circuits, and the loss of behavioral flexibility typical of early HD might largely depend on cell-type specific plastic abnormalities.     

Corticostriatal synaptic plasticity alterations in the R6/1 transgenic mouse model of Huntington's disease

Huntington's disease (HD) is a genetic neurodegenerative condition characterized by abnormal dopamine (DA)–glutamate interactions, severe alterations in motor control, and reduced behavioral flexibility. Experimental models of disease show that during symptomatic phases, HD shares with other hyperkinetic disorders the loss of synaptic depotentiation in the striatal spiny projection neurons (SPNs). Here we test the hypothesis that corticostriatal long-term depression (LTD), a well-conserved synaptic scaling down response to environmental stimuli, is also altered in symptomatic male R6/1 mice, a HD model with gradual development of symptoms. In vitro patch-clamp and intracellular recordings of corticostriatal slices from R6/1 mice confirm that, similar to other models characterized by hyperkinesia and striatal DA D1 receptor pathway dysregulation, once long-term potentiation (LTP) is induced, synaptic depotentiation is lost. Our new observations show that activity-dependent LTD was abolished in SPNs of mutant mice. In an experimental condition in which N-methyl-d -aspartate (NMDA) receptors are normally not recruited, in vitro bath application of DA revealed an abnormal response of D1 receptors that caused a shift in synaptic plasticity direction resulting in an NMDA-dependent LTP. Our results demonstrate that corticostriatal LTD is lost in R6/1 mouse model and confirm the role of aberrant DA–glutamate interactions in the alterations of synaptic scaling down associated with HD symptoms.     

Selective remodeling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion

The widely held view that the pathophysiology of Parkinson's disease arises from an under‐activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre‐dependent channelrhodopsin‐2 (ChR2) the PfN of Vglut2‐Cre mice that were dopamine‐depleted with 6‐hydroxydopamine (6‐OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6‐OHDA‐treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6‐OHDA lesions failed to affect short‐term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA‐to‐AMPA ratios at PfN synapses—that were significantly larger than NMDA‐to‐AMPA ratios at cortical synapses—were reduced by 6‐OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D₅ dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short‐term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de‐potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.     

Increased GABAergic function in mouse models of Huntington's disease: reversal by BDNF

Huntington's disease (HD) is characterized by loss of striatal gamma-aminobutyric acid (GABA)ergic medium-sized spiny projection neurons (MSSNs), whereas some classes of striatal interneurons are relatively spared. Striatal interneurons provide most of the inhibitory synaptic input to MSSNs and use GABA as their neurotransmitter. We reported previously alterations in glutamatergic synaptic activity in the R6/2 and R6/1 mouse models of HD. In the present study, we used whole-cell voltage clamp recordings to examine GABAergic synaptic currents in MSSNs from striatal slices in these two mouse models compared to those in age-matched control littermates. The frequency of spontaneous GABAergic synaptic currents was increased significantly in MSSNs from R6/2 transgenics starting around 5-7 weeks (when the overt behavioral phenotype begins) and continuing in 9-14-week-old mice. A similar increase was observed in 12-15-month-old R6/1 transgenics. Bath application of brain-derived neurotrophic factor, which is downregulated in HD, significantly reduced the frequency of spontaneous GABAergic synaptic currents in MSSNs from R6/2 but not control mice at 9-14 weeks. Increased GABA current densities also occurred in acutely isolated MSSNs from R6/2 animals. Immunofluorescence demonstrated increased expression of the ubiquitous alpha1 subunit of GABA(A) receptors in MSSNs from R6/2 animals. These results indicate that increases in spontaneous GABAergic synaptic currents and postsynaptic receptor function occur in parallel to progressive decreases in glutamatergic inputs to MSSNs. In conjunction, both changes will severely alter striatal outputs to target areas involved in the control of movement.     

Altered cortico-striatal synaptic plasticity and related behavioural impairments in reeler mice

Reelin-deficient mice have been used to investigate the role of this extracellular protein in cortico-striatal plasticity and striatum-related behaviours. Here we show that a repetitive electrical stimulation of the cortico-striatal pathway elicited long-term potentiation (LTP) in homozygous reeler (rl/rl) mice, while causing long-term depression in their wild-type (+/+) littermates. The N-methyl-D-aspartic acid (NMDA) receptor antagonist D-(-)-2 amino-5-phosphonopentanoic acid prevented the induction of LTP in (rl/rl) mice, thus confirming that this form of synaptic plasticity was NMDA receptor-dependent. Interestingly, in the presence of tiagabine, a blocker of gamma-aminobutyric acid (GABA) re-uptake system, the probability that (rl/rl) mice showed LTP decreased significantly, thus suggesting an impaired GABAergic transmission in reeler mutants. Consistent with this view, a decreased density of parvalbumin-positive GABAergic striatal interneurons was found in (rl/rl) mice in comparison to (+/+) mice. Finally, compatible with their abnormal striatal function (rl/rl) mice exhibited procedural learning deficits. Our data, showing alterations in cortico-striatal plasticity largely depending on a depressed GABAergic tone, delineate a mechanism whereby the lack of reelin may affect cognitive functions.     

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     

NMDA receptor function in mouse models of Huntington disease.

Huntington disease (HD) is an autosomal dominant disorder in which degeneration of medium-sized spiny striatal neurons occurs. The HD gene and the protein it encodes, huntingtin, have been identified but their functions remain unknown. Transgenic mouse models for HD have been developed and we examined responses of medium-sized striatal neurons recorded in vitro to application of N-methyl-D-aspartate (NMDA) in two of these. The first model (R6/2) expresses exon 1 of the human HD gene with approximately 150 CAG repeats. In the R6/2 an enhancement of currents induced by selective activation of NMDA receptors as well as an enhancement of intracellular Ca(2+) flux occurred in both presymptomatic and symptomatic mice. These alterations appeared specific for the NMDA receptor because alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated currents were reduced in symptomatic R6/2s. In R6/2 animals there were parallel increases in NMDA-R1 and decreases in NMDA-R2A/B subunit proteins as established by immunohistochemistry. The second model (YAC72) contains human genomic DNA spanning the full-length gene and all its regulatory elements with 72 CAG repeats. The phenotypical expression of the disorder develops more gradually than in the R6/2. In YAC72 mice we found similar but less marked increases in responses of medium-sized striatal neurons to NMDA. These findings indicate that alterations in NMDA receptor function may predispose striatal neurons to excitotoxic damage, leading to subsequent neuronal degeneration and underscore the functional importance of NMDA receptors in HD.     

Nicotinic activity layer specifically modulates synaptic potentiation in the mouse insular cortex

Nicotinic acetylcholine receptors (nAChRs) in the insular cortex play an important role in nicotine addiction, but its cellular and synaptic mechanisms underlying nicotine addiction still remain unresolved. In layer 5 pyramidal neurons of the mouse insular cortex, activation of nAChRs suppresses synaptic potentiation through enhancing GABAergic synaptic transmission via activation of β2‐containing nAChRs in non‐fast‐spiking (non‐FS) interneurons. However, it has not been addressed whether and how activation of nAChRs modulates synaptic plasticity in layers 3 and 6 pyramidal neurons of the insular cortex. In this study, I demonstrate that activation of nAChRs oppositely modulates synaptic potentiation in layers 3 and 6 pyramidal neurons of the insular cortex. In layer 3 pyramidal neurons, activation of nAChRs depressed synaptic potentiation induced by combination of presynaptic stimulation with postsynaptic depolarization (paired training) through enhancing GABAergic synaptic transmission via activation of β2‐containing nAChRs in non‐FS interneurons. By contrast, in layer 6 pyramidal neurons, activation of nAChRs enhanced synaptic potentiation through activating postsynaptic β2‐containing nAChRs. These results indicate, in different layers of the mouse insular cortex, paired training‐induced synaptic potentiation is oppositely regulated by activation of nAChRs which are located on GABAergic interneurons (layer 3) and on pyramidal neurons (layer 6). Thus, layer‐specific modulation of synaptic potentiation may be involved in cellular and synaptic mechanisms of insular cortical changes in nicotine addiction.     

Striatal spiny neurons and cholinergic interneurons express differential ionotropic glutamatergic responses and vulnerability: Implications for ischemia and Huntington's disease

Striatal spiny neurons are selectively vulnerable in Huntington's disease (HD) and ischemia, whereas large aspiny (LA) cholinergic interneurons of the striatum are spared in these pathological conditions. We have investigated whether a different sensitivity to ionotropic glutamatergic agonists might account for this differential vulnerability. Intracellular recordings were obtained from morphologically identified striatal spiny neurons and LA cholinergic interneurons by using a rat brain slice preparation. The two striatal neuronal subtypes had strikingly different intrinsic membrane properties. Both subtypes responded to cortical stimulation with excitatory postsynaptic potentials: these potentials, however, had a different time course and pharmacology in the two classes of cells. Interestingly, membrane depolarizations and inward currents produced by exogenous glutamate receptor agonists (AMPA, kainate, and NMDA) were remarkably larger in spiny neurons than in LA interneurons. Moreover, concentrations of agonists producing reversible membrane changes in LA interneurons caused irreversible depolarizations in spiny cells. Our data suggest that the different physiological responses induced by the activation of ionotropic glutamate receptors may account for the cell type-specific vulnerability of striatal neurons in ischemia and HD.     

Tissue plasminogen activator is required for corticostriatal long-term potentiation

Several experimental data indicate that tissue plasminogen activator (tPA) is involved in memory formation and synaptic plasticity in different brain areas. In the attempt to highlight the role of this serine protease in striatal neuron activity, mice lacking tPA have been used for electrophysiological, immunohistochemical and Western blot experiments. Disruption of tPA gene prevented corticostriatal long-term potentiation, an NMDA-dependent form of synaptic plasticity requiring the stimulation of both dopamine and acetylcholine receptors. Spontaneous and evoked glutamatergic transmission was intact in the striatum of tPA-deficient mice, as was the nigrostriatal dopamine innervation and the expression of dopamine D1 receptors. Conversely, the sensitivity of striatal cholinergic interneurons to dopamine D1 receptor stimulation was lost in these mutants, suggesting that tPA facilitates long-term potentiation (LTP) induction in the striatum by favouring the D1 receptor-mediated excitation of acetylcholine-producing interneurons. The demonstration that tPA ablation interferes with the induction of corticostriatal LTP and with the dopamine receptor-mediated control of cholinergic interneurons might help to explain the altered striatum-dependent learning deficits observed in tPA-deficient mice and provides new insights into the molecular mechanisms underlying synaptic plasticity in the striatum.     

Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction

Although glutamate transporters maintain low extracellular levels of the excitatory neurotransmitter glutamate in the nervous system, little is known about their roles in synaptic plasticity. Here, using knockout mice lacking GLT-1, that is the most abundant glial subtype of glutamate transporters, we showed that long-term potentiation (LTP) induced by tetanic stimulation in mutant mice was impaired in the hippocampal CA1 region. When tetanic stimulation was applied in the presence of low concentrations of an N-methyl-D-aspartate (NMDA) receptor antagonist, the impairment was overcome. Consistent with these results, the increased glutamate in the synaptic cleft of mutant mice preferentially activated NMDA receptors. Furthermore, analyses of mutant mice revealed that the magnitude of NMDA receptor-dependent transient synaptic potentiation during low-frequency stimulation depended on the concentration of glutamate in the synaptic cleft. These findings suggest that GLT-1 plays critical roles in LTP induction, as well as in short-term potentiation, through regulation of extracellular levels of glutamate, which enables appropriate NMDA receptor activation.     

Permissive role of interneurons in corticostriatal synaptic plasticity

Two different forms of synaptic plasticity have been found at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Striatal LTD and LTP are evoked following the repetitive stimulation of corticostriatal fibers and are dependent on the glutamate ionotropic receptor subtype activated. Recent experimental evidence indicates that two different subtypes of interneurons attend in the correct processing of information flow arising from the cortex and leading to striatal LTD or LTP. Acetylcholine (Ach) and nitric oxide (NO) producing striatal interneurons, in fact, are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exerts a feed-forward control of the excitability of striatal projection neurons ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse.     

Striatal glutamatergic mechanisms and extrapyramidal movement disorders

The nonphysiologic stimulation of striatal dopaminergic receptors, as a result of disease- or drug-related denervation or intermittent excitation, triggers adaptive responses in the basal ganglia which contribute to the appearance of parkinsonian symptoms and later to the dyskinesias and other alterations in motor response associated with dopaminergic therapy. Current evidence suggests that these altered responses involve activation of signal transduction cascades in striatal medium spiny neurons linking dopaminergic to coexpressed ionotropic glutamatergic receptors of the N-methyl-D-aspartate (NMDA) and Alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) classes. These intraneuronal signaling pathways appear capable of modifying the phosphorylation state of NMDA and AMPA receptor subunits; resultant sensitization enhances cortical glutamatergic input which in turn modifies striatal output in ways that compromise motor behavior. The regulation of these spiny neuron glutamate receptors can also be affected by the activation state of coexpressed nondopaminergic receptors as well as by changes associated with Huntington's disease. These observations lend new insight into molecular mechanisms contributing to the integration of synaptic inputs to spiny neurons. They also suggest novel approaches to the pharmacotherapy of extrapyramidal motor dysfunction.     

Dopamine, acetylcholine and nitric oxide systems interact to induce corticostriatal synaptic plasticity

Two distinct forms of synaptic plasticity have been described at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Along with the massive glutamatergic inputs originating from the cortex, striatal neurons receive a myriad of other synaptic contacts arising from different sources. In particular, while the nigrostriatal pathway provides this brain area with dopamine (DA), intrinsic circuits are the main source of acetylcholine (ACh) and nitric oxide (NO). The three neurotransmitter systems interact with each other to determine whether corticostriatal LTP or LTD is triggered in response to repetitive synaptic stimulation. Two distinct subtypes of striatal interneurons produce ACh and NO in the striatum. These interneurons are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exert a feedforward control of the excitability of striatal projection neurons by ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse. The integrative action exerted by striatal projection neurons on the converging information arising from the cortex, nigral DA neurons, and from ACh- and NO-producing interneurons dictates the final output of the striatum to the other structures of the basal ganglia.     

Repetitive febrile seizures in rat pups cause long-lasting deficits in synaptic plasticity and NR2A tyrosine phosphorylation

Adult rats with early-life frequently repetitive febrile seizures (FRFS), but not single febrile seizure (SFS), exhibited impaired performance in inhibitory avoidance tasks but without significant hippocampal neuronal loss. The mechanisms of long-term memory impairment in the hippocampus of adult rats with early-life FRFS remain unknown. Using a heated-air febrile seizures (FS) paradigm, male rat pups were subjected to single or nine episodes of brief FS at days 10 to 12 postpartum. We found that early-life FRFS led to long-term bidirectional modulation in hippocampal synaptic plasticity, i.e., impaired long-term potentiation and facilitated long-term depression. Three hours after inhibitory avoidance training, phosphorylation of hippocampal extracellular signal-regulated kinase (ERK) 1/2 was significantly less in the FRFS group than in controls. Furthermore, there was a selective alteration in NMDA receptor-mediated ERK1/2 phosphorylation in the hippocampus of the FRFS group. Although the expression levels of NMDA receptor subunits and interaction of NMDA receptor and postsynaptic density 95 did not alter quantitatively, there was a specific alteration in NR2A, but not NR2B, subunit tyrosine phosphorylation after NMDA stimulation in the FRFS group. These data offer a potential molecular explanation for the hippocampus-dependent memory deficits observed in the rats with early-life FRFS.     

Dopamine-mediated regulation of corticostriatal synaptic plasticity

The striatum represents the main input into the basal ganglia. Neurons projecting from the striatum receive a large convergence of afferents from all areas of the cortex and transmit neural information to the basal ganglia output structures. Corticostriatal transmission is essential in the regulation of voluntary movement, in addition to behavioural control, cognitive function and reward mechanisms. Long-term potentiation (LTP) and long-term depression (LTD), the two main forms of synaptic plasticity, are both represented at corticostriatal synapses and strongly depend on the activation of dopamine receptors. Here, we discuss possible feedforward and feedback mechanisms by which striatal interneurons, in association with striatal spiny neurons and endogenous dopamine, influence the formation and maintenance of both LTP and LTD. We also propose a model in which the spontaneous membrane oscillations of neurons projecting from the striatum (named 'up' and 'down' states), in addition to the pattern of release of endogenous dopamine, bias the synapse towards preferential induction of LTP or LTD. Finally, we discuss how endogenous dopamine crucially influences changes in synaptic plasticity induced by pathological stimuli, such as energy deprivation.     

Before or after does it matter? Different protocols of environmental enrichment differently influence motor, synaptic and structural deficits of cerebellar origin

Cerebellar compensation is a reliable model of lesion-induced plasticity occurring through profound synaptic and neurochemical modifications in cortical and sub-cortical regions. As the recovery from cerebellar deficits progresses, the firstly enhanced glutamate striatal transmission is then normalized. The time course of cerebellar compensation and the concomitant striatal modifications might be influenced by protocols of environmental enrichment (EE) differently timed in respect to cerebellar lesion. In the present study, we analyzed the effects of different EE protocols on postural and locomotor behaviors (by means of a neurological rating scale), and on striatal synaptic activity (by means of recordings of spontaneous glutamate-mediated excitatory postsynaptic currents (sEPSCs)) and on morphological correlates (by means of density and dendritic length of Fast Spiking (FS) interneurons) following hemicerebellectomy (HCb) in rats. Cerebellar motor deficits were reduced faster in the enriched animals in comparison to standard housed HCbed rats. The beneficial influence of EE was higher in the animals enriched before the HCb than in rats enriched only after the lesion. In parallel, the HCb-induced increase in striatal sEPSCs was not observed in rats enriched before HCb and attenuated in rats enriched after HCb. Furthermore, the EE prevented the shrinkage of dendritic arborization of FS striatal interneurons. Also this effect was more marked in animals enriched before than after the HCb. The exposure to EE exerted either neuro-protective or therapeutic actions on the cerebellar deficits. The experience-dependent changes of the synaptic and neuronal connectivity observed in the striatal neurons may represent one of the mechanisms through which the enrichment facilitates functional compensation following the cerebellar damage.     

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.     

Plasticity of inhibitory synaptic network interactions in the lateral amygdala upon fear conditioning in mice

After fear conditioning, plastic changes of excitatory synaptic transmission occur in the amygdala. Fear‐related memory also involves the GABAergic system, although no influence on inhibitory synaptic transmission is known. In the present study we assessed the influence of Pavlovian fear conditioning on the plasticity of GABAergic synaptic interactions in the lateral amygdala (LA) in brain slices prepared from fear‐conditioned, pseudo‐trained and naïve adult mice. Theta‐burst tetanization of thalamic afferent inputs to the LA evoked an input‐specific potentiation of inhibitory postsynaptic responses in projection neurons; the cortical input was unaffected. Philanthotoxin (10 µm ), an antagonist of Ca²⁺‐permeable AMPA receptors, disabled this plastic phenomenon. Surgical isolation of the LA, extracellular application of a GABA_B receptor antagonist (CGP 55845A, 10 µm ) or an NMDA receptor antagonist (APV, 50 µm ), or intracellular application of BAPTA (10 mm ), did not influence the plasticity. The plasticity also showed as a potentiation of monosynaptic excitatory responses in putative GABAergic interneurons. Pavlovian fear conditioning, but not pseudo‐conditioning, resulted in a significant reduction in this potentiation that was evident 24 h after training. Two weeks after training, the potentiation returned to control levels. In conclusion, a reduction in potentiation of inhibitory synaptic interactions occurs in the LA and may contribute to a shift in synaptic balance towards excitatory signal flow during the processes of fear‐memory acquisition or consolidation.     

Regulation of synaptic plasticity by mGluR1 studied in vivo in mGluR1 mutant mice

The role of the metabotropic glutamate receptor 1 (mGluR₁) in synaptic plasticity was investigated in vivo in the intact hippocampus of mutant mice lacking this receptor. In a previous study we showed reduced long-term potentiation (LTP) in the dentate gyrus of mGluR₁ −/− mice in vivo, but not when LTP was studied in a slice preparation. A possible explanation of this difference is that dentate neurons receive more inhibitory synaptic drive in vivo than in slice preparation where many inhibitory axon collaterals are lost. We report here that another form of synaptic plasticity, paired-pulse depression of the population spike, is also abnormal in the dentate gyrus of mGluR₁-deficient mice when tested in vivo. In wild-type mice, stimulation of the medial perforant path produced paired-pulse depression of inter-pulse intervals (IPIs) up to 30 ms. Mutant mGluR₁, on the other hand, showed a significantly longer IPI depression, up to 50 ms. Paired-pulse depression results from the activation of inhibitory interneurons. The GABA_B agonist baclofen, acting presynaptically on the GABA interneurons, attenuated paired-pulse depression and allowed for a normal and stable LTP in mGluR₁ mutant mice. These findings suggest an indirect role for mGluR₁ in synaptic plasticity via a regulation of GABA inhibition.