Role of ß3-adrenergic receptor in the modulation of synaptic transmission and plasticity in mouse cerebellar cortex.

Convergent lines of evidence have recently highlighted ß3-adrenoreceptors (ARs) as a potentially critical target in the regulation of nervous and behavioral functions, including memory consolidation, anxiety, and depression. Nevertheless, the role of ß3-ARs in the cerebellum has been never investigated. To address this issue, we first examined the effects of pharmacological manipulation of ß3-ARs on motor learning in mice. We found that blockade of ß3-ARs by SR 59230A impaired the acquisition of the rotarod task with no effect on general locomotion. Since the parallel fiber-Purkinje cell (PF-PC) synapse is considered to be the main cerebellar locus of motor learning, we assessed ß3-AR modulatory action on this synapse as well as its expression in cerebellar slices. We demonstrate, for the first time, a strong expression of ß3-ARs on Purkinje cell soma and dendrites. In addition, whole-cell patch-clamp recordings revealed that bath application of ß3-AR agonist CL316,243 depressed the PF-PC excitatory postsynaptic currents via a postsynaptic mechanism mediated by the PI3K signaling pathway. Application of CL316,243 also interfered with the expression of PF long-term potentiation, whereas SR 59230A prevented the induction of LTD at PF-PC synapse. These results underline the critical role of ß3-AR on cerebellar synaptic transmission and plasticity and provide a new mechanism for adrenergic modulation of motor learning.

GIRK1-Mediated Inwardly Rectifying Potassium Current Is a Candidate Mechanism Behind Purkinje Cell Excitability, Plasticity, and Neuromodulation.

G-protein-coupled inwardly rectifying potassium (GIRK) channels contribute to the resting membrane potential of many neurons and play an important role in controlling neuronal excitability. Although previous studies have revealed a high expression of GIRK subunits in the cerebellum, their functional role has never been clearly described. Using patch-clamp recordings in mice cerebellar slices, we examined the properties of the GIRK currents in Purkinje cells (PCs) and investigated the effects of a selective agonist of GIRK1-containing channels, ML297 (ML), on PC firing and synaptic plasticity. We demonstrated that GIRK channel activation decreases the PC excitability by inhibiting both sodium and calcium spikes and, in addition, modulates the complex spike response evoked by climbing fiber stimulation. Our results indicate that GIRK channels have also a marked effect on synaptic plasticity of the parallel fiber-PC synapse, as the application of ML297 increased the expression of LTP while preventing LTD. We, therefore, propose that the recruitment of GIRK channels represents a crucial mechanism by which neuromodulators can control synaptic strength and membrane conductance for proper refinement of the neural network involved in memory storage and higher cognitive functions.

Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels.

L1 (also known as L1CAM) is a trans-membrane glycoprotein mediating neuron-neuron adhesion through homophilic and heterophilic interactions. Although experimental evidence has implicated L1 in axonal outgrowth, fasciculation and pathfinding, its contribution to voltage-gated Na(+) channel function and membrane excitability has remained unknown. Here, we show that firing rate, single cell spiking frequency and Na(+) current density are all reduced in hippocampal excitatory neurons from L1-deficient mice both in culture and in slices owing to an overall reduced membrane expression of Na(+) channels. Remarkably, normal firing activity was restored when L1 was reintroduced into L1-deficient excitatory neurons, indicating that abnormal firing patterns are not related to developmental abnormalities, but are a direct consequence of L1 deletion. Moreover, L1 deficiency leads to impairment of action potential initiation, most likely due to the loss of the interaction of L1 with ankyrin G that produces the delocalization of Na(+) channels at the axonal initial segment. We conclude that L1 contributes to functional expression and localization of Na(+) channels to the neuronal plasma membrane, ensuring correct initiation of action potential and normal firing activity.

Down regulation of pro-inflammatory pathways by tanshinone IIA and cryptotanshinone in a non-genetic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a common form of dementia mainly characterized by the deposition of neurofibrillary tangles and ß-amyloid (Aß) peptides in the brain. Additionally, increasing evidence demonstrates that a neuro-inflammatory state plays a key role in the development of this disease. Beside synthetic drugs, the use of natural compounds represents an alternative for the development of new potential drugs for the treatment of AD. Among these, the root of Salvia miltiorhiza Bunge (also known as Danshen) used for the treatment of cardiovascular, cerebrovascular disease and CNS functional decline in Chinese traditional medicine is one of the most representative examples. We therefore evaluated the effects of tanshinone IIA (TIIA) and cryptotanshinone (CRY) (the two major lipophilic compounds of Danshen) in a non-genetic mouse model of ß-amyloid (Aß)-induced AD, which is mainly characterized by reactive gliosis and neuro-inflammation in the brain. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aß1-42 peptide (3µg/3µl) and after with TIIA and CRY (1, 3, or 10mg/kg) intraperitoneally (i.p.) 3 times weekly for 21days following the induction of experimental AD. Spatial working memory was assessed as a measure of short-term memory in mice, whereas the level of GFAP, S100ß, COX-2, iNOS and NF-kBp65 monitored by western blot and ELISA assay, were selected as markers of reactive gliosis and neuro-inflammation. Finally, by docking studies, the modulation of key pro-inflammatory enzymes and pathways involved in the AD-related neuro-inflammation were also investigated. Results indicate that TIIA and CRY alleviate memory decline in Aß1-42-injected mice, in a dose dependent manner. Moreover, the analysis of gliosis-related and neuro-inflammatory markers in the hippocampal tissues reveal a remarkable reduction in the expression of GFAP, S100ß, COX-2, iNOS and NF-kBp65 after CRY (10mg/kg) treatment. These effects were less evident, but still significant, after TIIA (10mg/kg). Finally, in silico analysis also revealed that both compounds were able to interact with the binding sites of NF-kBp65 endorsing the data from biochemical analysis. We conclude that TIIA and CRY display anti-inflammatory and neuroprotective effect in a non-genetic mouse model of AD, thus playing a role in slowing down the course and onset of AD.

REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability.

Intrinsic homeostasis enables neuronal circuits to maintain activity levels within an appropriate range by modulating neuronal voltage-gated conductances, but the signalling pathways involved in this process are largely unknown. We characterized the process of intrinsic homeostasis induced by sustained electrical activity in cultured hippocampal neurons based on the activation of the Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). We showed that 4-aminopyridine-induced hyperactivity enhances the expression of REST/NRSF, which in turn, reduces the expression of voltage-gated Na(+) channels, thereby decreasing the neuronal Na(+) current density. This mechanism plays an important role in the downregulation of the firing activity at the single-cell level, re-establishing a physiological spiking activity in the entire neuronal network. Conversely, interfering with REST/NRSF expression impaired this homeostatic response. Our results identify REST/NRSF as a critical factor linking neuronal activity to the activation of intrinsic homeostasis and restoring a physiological level of activity in the entire neuronal network.

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway.

Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development.

Maturation, Refinement, and Serotonergic Modulation of Cerebellar Cortical Circuits in Normal Development and in Murine Models of Autism.

The formation of the complex cerebellar cortical circuits follows different phases, with initial synaptogenesis and subsequent processes of refinement guided by a variety of mechanisms. The regularity of the cellular and synaptic organization of the cerebellar cortex allowed detailed studies of the structural plasticity mechanisms underlying the formation of new synapses and retraction of redundant ones. For the attainment of the monoinnervation of the Purkinje cell by a single climbing fiber, several signals are involved, including electrical activity, contact signals, homosynaptic and heterosynaptic interaction, calcium transients, postsynaptic receptors, and transduction pathways. An important role in this developmental program is played by serotonergic projections that, acting on temporally and spatially regulated postsynaptic receptors, induce and modulate the phases of synaptic formation and maturation. In the adult cerebellar cortex, many developmental mechanisms persist but play different roles, such as supporting synaptic plasticity during learning and formation of cerebellar memory traces. A dysfunction at any stage of this process can lead to disorders of cerebellar origin, which include autism spectrum disorders but are not limited to motor deficits. Recent evidence in animal models links impairment of Purkinje cell function with autism-like symptoms including sociability deficits, stereotyped movements, and interspecific communication by vocalization.

Evidence of Presynaptic Localization and Function of the c-Jun N-Terminal Kinase.

The c-Jun N-terminal kinase (JNK) is part of a stress signalling pathway strongly activated by NMDA-stimulation and involved in synaptic plasticity. Many studies have been focused on the post-synaptic mechanism of JNK action, and less is known about JNK presynaptic localization and its physiological role at this site. Here we examined whether JNK is present at the presynaptic site and its activity after presynaptic NMDA receptors stimulation. By using N-SIM Structured Super Resolution Microscopy as well as biochemical approaches, we demonstrated that presynaptic fractions contained significant amount of JNK protein and its activated form. By means of modelling design, we found that JNK, via the JBD domain, acts as a physiological effector on T-SNARE proteins; then using biochemical approaches we demonstrated the interaction between Syntaxin-1-JNK, Syntaxin-2-JNK, and Snap25-JNK. In addition, taking advance of the specific JNK inhibitor peptide, D-JNKI1, we defined JNK action on the SNARE complex formation. Finally, electrophysiological recordings confirmed the role of JNK in the presynaptic modulation of vesicle release. These data suggest that JNK-dependent phosphorylation of T-SNARE proteins may have an important functional role in synaptic plasticity.

Cysteine Prevents the Reduction in Keratin Synthesis Induced by Iron Deficiency in Human Keratinocytes.

L-cysteine is currently recognized as a conditionally essential sulphur amino acid. Besides contributing to many biological pathways, cysteine is a key component of the keratin protein by its ability to form disulfide bridges that confer strength and rigidity to the protein. In addition to cysteine, iron represents another critical factor in regulating keratins expression in epidermal tissues, as well as in hair follicle growth and maturation. By focusing on human keratinocytes, the aim of this study was to evaluate the effect of cysteine supplementation as nutraceutical on keratin biosynthesis, as well as to get an insight on the interplay of cysteine availability and cellular iron status in regulating keratins expression in vitro. Herein we demonstrate that cysteine promotes a significant up-regulation of keratins expression as a result of de novo protein synthesis, while the lack of iron impairs keratin expression. Interestingly, cysteine supplementation counteracts the adverse effect of iron deficiency on cellular keratin expression. This effect was likely mediated by the up-regulation of transferrin receptor and ferritin, the main cellular proteins involved in iron homeostasis, at last affecting the labile iron pool. In this manner, cysteine may also enhance the metabolic iron availability for DNA synthesis without creating a detrimental condition of iron overload. To the best of our knowledge, this is one of the first study in an in vitro keratinocyte model providing evidence that cysteine and iron cooperate for keratins expression, indicative of their central role in maintaining healthy epithelia.

The Anticonvulsant Activity of a Flavonoid-Rich Extract from Orange Juice Involves both NMDA and GABA-Benzodiazepine Receptor Complexes.

The usage of dietary supplements and other natural products to treat neurological diseases has been growing over time, and accumulating evidence suggests that flavonoids possess anticonvulsant properties. The aim of this study was to examine the effects of a flavonoid-rich extract from orange juice (OJe) in some rodent models of epilepsy and to explore its possible mechanism of action. The genetically audiogenic seizures (AGS)-susceptible DBA/2 mouse, the pentylenetetrazole (PTZ)-induced seizures in ICR-CD1 mice and the WAG/Rij rat as a genetic model of absence epilepsy with comorbidity of depression were used. Our results demonstrate that OJe was able to exert anticonvulsant effects on AGS-sensible DBA/2 mice and to inhibit PTZ-induced tonic seizures, increasing their latency. Conversely, it did not have anti-absence effects on WAG/Rij rats. Our experimental findings suggest that the anti-convulsant effects of OJe are likely mediated by both an inhibition of NMDA receptors at the glycine-binding site and an agonistic activity on benzodiazepine-binding site at GABAA receptors. This study provides evidences for the antiepileptic activity of OJe, and its results could be used as scientific basis for further researches aimed to develop novel complementary therapy for the treatment of epilepsy in a context of a multitarget pharmacological strategy.

Maternal treatment with sodium butyrate reduces the development of autism-like traits in mice offspring.

Several studies indicate a relationship between maternal gut microbiota alteration and increased risk of autism spectrum disorders (ASD) in offspring. The possibility of compensating for such metabolic dysfunction at a very early stage of disease via maternal treatment has not been enough explored. Here, we examined in BTBR mouse model of ASD the effect of maternal treatment with the gut microbial metabolite butyrate (BUT) on the behavioral and synaptic plasticity deficits in juvenile and adult offspring. We show that BUT treatment of BTBR dams rescues the social and partially the repetitive behavior deficits in the offspring. In addition, maternal BUT implementation prevents the cerebellar cortex hypertrophy as well as the Purkinje cells firing and long-term synaptic plasticity deficits in BTBR mice. Our results demonstrate, for the first time, that maternal BUT treatment can improve ASD-like symptoms in offspring thus providing new directions for the early treatment of neurodevelopmental disorders.

Nitric oxide stimulates NCX1 and NCX2 but inhibits NCX3 isoform by three distinct molecular determinants.

In this study, the role of nitric oxide (NO) in the modulation of the activity of NCX1, NCX2, and NCX3 exchangers was investigated in baby hamster kidney cells singly transfected with each of these isoforms by single-cell Fura-2-microfluorometry and patch clamp. Furthermore, the molecular determinants of NO on each isoform were identified by deletion, site-directed mutagenesis, and chimera strategies. Our data revealed four main findings. First, the NO-donor S-nitroso-N-acetylpenicillamine (SNAP; 10 nM) and the NO-precursor L-arginine (10 mM) were both able to increase NCX1 activity in a cGMP-independent way. Moreover, within the amino acid sequence 723 to 734 of the f-loop, Cys730 resulted as the target of NO on NCX1. Second, SNAP and L-arginine were able to increase NCX2 activity, but this effect was prevented by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). In addition, the membrane-permeable 8-bromoguanosine-cGMP alone was able to mimic the stimulatory effect of the gaseous mediator, suggesting the involvement of a cGMP-dependent mechanism. Within the amino acid sequence 699 to 744 of the f-loop, Ser713 was the NO molecular determinant on the NCX2 protein; Third, NCX3 activity was instead down-regulated by NO in a cGMP-independent manner. This NO-inhibitory action was exerted at the level of Cys156 in the α1-region outside the f-loop. Finally, the activity of the two NCX3 chimeras-obtained by the replacement of the NO-insensitive NCX3 region with the homologous NO-sensitive segments of NCX1 or NCX2-was potentiated by SNAP. Together, the present data demonstrate that NO differently regulates the activity of the three gene products NCX1, NCX2, and NCX3 by modulating specific molecular determinants.

Roles for the Dorsal Striatum in Aversive Behavior.

The ability to identify and avoid environmental stimuli that signal danger is essential to survival. Our understanding of how the brain encodes aversive behaviors has been primarily focused on roles for the amygdala, hippocampus (HIPP), prefrontal cortex, ventral midbrain, and ventral striatum. Relatively little attention has been paid to contributions from the dorsal striatum (DS) to aversive learning, despite its well-established role in stimulus-response learning. Here, we review studies exploring the role of DS in aversive learning, including different roles for the dorsomedial and dorsolateral striatum in Pavlovian fear conditioning as well as innate and inhibitory avoidance (IA) behaviors. We outline how future investigation might determine specific contributions from DS subregions, cell types, and connections that contribute to aversive behavior.

Molecular pharmacology of the amiloride analog 3-amino-6-chloro-5-[(4-chloro-benzyl)amino]-n-[[(2,4-dimethylbenzyl)-amino]iminomethyl]-pyrazinecarboxamide (CB-DMB) as a pan inhibitor of the Na+-Ca2+ exchanger isoforms NCX1, NCX2, and NCX3 in stably transfected cells.

With the help of single-cell microflorimetry, (45)Ca(2+) radiotracer fluxes, and patch-clamp in whole-cell configuration, we examined the effect of the amiloride derivative 3-amino-6-chloro-5-[(4-chloro-benzyl)amino]-N-[[(2,4-dimethylbenzyl)amino]iminomethyl]-pyrazinecarboxamide (CB-DMB) on the activity of the three isoforms of the Na(+)/Ca(2+) exchanger (NCX) and on several other membrane currents including voltage- and pH-sensitive ones. This amiloride analog suppressed the bidirectional activity of all NCX isoforms in a concentration-dependent manner. The IC(50) values of CB-DMB were in the nanomolar range for the outward and the inward components of the bidirectional NCX1, NCX2, and NCX3 activity. Deletion mutagenesis showed that CB-DMB inhibited NCX activity mainly at level of the f-loop but not through the interaction with Gly833 located at the level of the alpha(2) repeat. On the other hand, CB-DMB suppressed in the micromolar range the other plasma membrane currents encoded by voltage-dependent Ca(2+) channels, tetrodotoxin-sensitive Na(+) channels, and pH-sensitive ASIC1a. Collectively, the data of the present study showed that CB-DMB, when used in the nanomolar range, is one of the most potent compounds that can block the activity of the three NCX isoforms when they work both in the forward and in the reverse modes of operation without interfering with other ionic channels.

Neutralization of IL-17 rescues amyloid-ß-induced neuroinflammation and memory impairment.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD-related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL-17 has not been well addressed. Herein, we investigate the effects of IL-17 neutralizing antibody (IL-17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid-ß (Aß)-induced neuroinflammation and memory impairment in mice. EXPERIMENTAL APPROACH: Aß1-42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL-17Ab via i.c.v. either at 1 h prior to Aß1-42 injection or IN 5 and 12 days after Aß1-42 injection. After 7 and 14 days of Aß1-42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas. KEY RESULTS: Pretreatment with IL-17Ab, given, i.c.v., markedly reduced Aß1-42 -induced neurodegeneration, improved memory function, and prevented the increase of pro-inflammatory mediators in a dose-dependent manner at 7 and 14 days. Similarly, the double IN administration of IL-17Ab after Aß1-42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines. CONCLUSION AND IMPLICATIONS: These findings suggest that the IL-17Ab reduced neuroinflammation and behavioural symptoms induced by Aß. The efficacy of IL-17Ab IN administration in reducing Aß1-42 neurodegeneration points to a possible future therapeutic approach in patients with AD. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

The Emerging Role of Altered Cerebellar Synaptic Processing in Alzheimer's Disease.

The role of the cerebellum in Alzheimer's disease (AD) has been neglected for a long time. Recent studies carried out using transgenic mouse models have demonstrated that amyloid-ß (Aß) is deposited in the cerebellum and affects synaptic transmission and plasticity, sometimes before plaque formation. A wide variability of motor phenotype has been observed in the different murine models of AD, without a consistent correlation with the extent of cerebellar histopathological changes or with cognitive deficits. The loss of noradrenergic drive may contribute to the impairment of cerebellar synaptic function and motor learning observed in these mice. Furthermore, cerebellar neurons, particularly granule cells, have been used as in vitro model of Aß-induced neuronal damage. An unexpected conclusion is that the cerebellum, for a long time thought to be somehow protected from AD pathology, is actually considered as a region vulnerable to Aß toxic damage, even at the early stage of the disease, with consequences on motor performance.

Motor coordination and synaptic plasticity deficits are associated with increased cerebellar activity of NADPH oxidase, CAMKII, and PKC at preplaque stage in the TgCRND8 mouse model of Alzheimer's disease.

Numerous studies indicate that the cerebellum undergoes structural and functional neurodegenerative changes in Alzheimer's disease. The purpose of this study was to examine the extent of cerebellar alterations at early, preplaque stage of the pathology in TgCRND8 mice through behavioral, electrophysiological, and molecular analysis. Balance beam test and foot-printing analysis revealed significant motor coordination and balance deficits in 2-month-old TgCRND8 mice compared to their littermates. Patch-clamp recordings performed on cerebellar slices of transgenic mice showed synaptic plasticity deficit and loss of noradrenergic modulation at parallel fiber-Purkinje cell synapse suggesting an early dysfunction of the cerebellar circuitry due to amyloid precursor protein overexpression. Finally, western blot analysis revealed an enhanced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47phox and p67phox as well as Ca2+/calmodulin-dependent protein kinase and protein kinase C alpha in the cerebellum of 2-month-old transgenic mice. Therefore, we propose the existence of self-sustaining feedback loop involving the formyl peptide receptor 2-reactive oxygen species-Ca2+/calmodulin-dependent protein kinase II-protein kinase C alpha pathway that may promote reactive oxygen species generation in the early stage of Alzheimer's disease and eventually contribute to the exacerbation of pathological phenotype.

Role of hippocampus in polymodal-cue guided tasks in rats.

To examine how signals from different sensory modalities are integrated to generate an appropriate goal-oriented behavior, we trained rats in an eight-arm radial maze to visit a cue arm provided with intramaze cues from different sensory modalities, i.e. visual, tactile and auditory, in order to obtain a reward. When the same rats were then examined on test trials in which the cue arm contained one of the stimuli that the animals were trained with (i.e. light, sound or rough sheet), they showed a significant impairment with respect to the performance on the polymodal-cue task. The contribution of the dorsal hippocampus to the acquisition and retention of polymodal-cue guided task was also examined. We found that rats with dorsal hippocampal lesions before training showed a significant deficit in the acquisition of polymodal-cue oriented task that improved with overtraining. The selective lesion of the dorsal hippocampus after training disrupted memory retention, but the animals' performance improved following retraining of the polymodal task. All hippocampal lesioned rats displayed an impaired performance on the unimodal test. These findings suggest that the dorsal hippocampus contributes to the processing of multimodal sensory information for the associative memory formation and consolidation.

Modulation, Plasticity and Pathophysiology of the Parallel Fiber-Purkinje Cell Synapse.

The parallel fiber-Purkinje cell (PF-PC) synapse represents the point of maximal signal divergence in the cerebellar cortex with an estimated number of about 60 billion synaptic contacts in the rat and 100,000 billions in humans. At the same time, the Purkinje cell dendritic tree is a site of remarkable convergence of more than 100,000 parallel fiber synapses. Parallel fiber activity generates fast postsynaptic currents via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and slower signals, mediated by mGlu1 receptors, resulting in Purkinje cell depolarization accompanied by sharp calcium elevation within dendritic regions. Long-term depression (LTD) and long-term potentiation (LTP) have been widely described for the PF-PC synapse and have been proposed as mechanisms for motor learning. The mechanisms of induction for LTP and LTD involve different signaling mechanisms within the presynaptic terminal and/or at the postsynaptic site, promoting enduring modification in the neurotransmitter release and change in responsiveness to the neurotransmitter. The PF-PC synapse is finely modulated by several neurotransmitters, including serotonin, noradrenaline and acetylcholine. The ability of these neuromodulators to gate LTP and LTD at the PF-PC synapse could, at least in part, explain their effect on cerebellar-dependent learning and memory paradigms. Overall, these findings have important implications for understanding the cerebellar involvement in a series of pathological conditions, ranging from ataxia to autism. For example, PF-PC synapse dysfunctions have been identified in several murine models of spino-cerebellar ataxia (SCA) types 1, 3, 5 and 27. In some cases, the defect is specific for the AMPA receptor signaling (SCA27), while in others the mGlu1 pathway is affected (SCA1, 3, 5). Interestingly, the PF-PC synapse has been shown to be hyper-functional in a mutant mouse model of autism spectrum disorder, with a selective deletion of Pten in Purkinje cells. However, the full range of methodological approaches, that allowed the discovery of the physiological principles of PF-PC synapse function, has not yet been completely exploited to investigate the pathophysiological mechanisms of diseases involving the cerebellum. We, therefore, propose to extend the spectrum of experimental investigations to tackle this problem.