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Functional outcome in patients with postanoxic encephalopathy after cardiac arrest (CA) often remains unclear, and there is a strong need of new prognostication measures. We aimed at investigating serum neurofilament light (NfL) chain concentration in patients with a postanoxic encephalopathy after CA and its prognostic potential. Serum samples were prospectively collected at different time points after CA in consecutive patients admitted to the intensive care unit (ICU) of Ticino Cardiocentre (Lugano, Switzerland) between June 2017 and March 2018. Serum NfL concentration was measured using a single molecule array (SIMOA) assay. The association of NfL levels with time to return of spontaneous circulation (ROSC), serum neuronal specific enolase (NSE) concentration, time between CA and sample collection, electroencephalogram (EEG) pattern and clinical outcome (death status at one month) were explored. Fourteen patients experiencing 15 CAs were included in the study (median age = 58 (57-68) years, 8 males). Median serum NfL concentration was 1027.0 (25.5-6033.7) pg/ml. There were positive associations between serum NfL and time to ROSC (rho = 0.60, p 0.0001), NSE concentration (rho = 0.76, p 0.0001), and severity of brain damage as estimated by EEG, with the highest concentrations measured in patients with suppressed electrical activity (14,954.0 [9006.0-25,364.0] pg/ml). Neurofilament light concentration remained high in samples collected up to 17 days after CA. Median NfL levels were higher among dead than alive patients at one month (6401.7 [3768.5-15,573.3] vs 25.5 [25.2-75.4] pg/ml). High NfL levels performed better than NSE in predicting death status at one month (NfL area under the curve (AUC) = 0.98, 95% confidence interval (CI) = 0.94-1.00; NSE AUC = 0.80, 95% CI = 0.67-0.94). These results support the potential inclusion of serum NfL in the battery of prognostication measures to be used in patients with postanoxic encephalopathy in ICU settings. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Brain plasticity is a lifelong process and involves both Hebbian and non-Hebbian synaptic plasticity. The latter, such as intrinsic plasticity and homeostatic synaptic plasticity or synaptic scaling, is thought to counteract Hebbian plasticity, in order to maintain a balanced network. Recent studies support the role of sleep in the regulation of homeostatic synaptic plasticity involved in memory and learning processes. Most evidence focus on the dependence of memory and plasticity in sleep mechanisms. Abnormal brain plasticity during sleep might be implicated in the development of movement disorders, particularly Parkinson's disease (PD) and dystonia. From that, the great interest to understand the underlying process of sleep in relation to movement disorders. The first objective of the review is to summarize the latest knowledge about brain plasticity. The second objective is to analyze the association between sleep, memory and brain plasticity. Finally, the review aims to assess the consequence of abnormal plasticity during PD and dystonia with a viewpoint on the underling pathogenesis of these disorders.

Summary Purpose: The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug-naive patients affected by temporal lobe epilepsy (TLE). Methods: We measured the levels of both AEA and the other endocannabinoid, 2-arachidonoylglycerol (2-AG), in the CSF of drug-naive patients with TLE. Results: A significant reduction of AEA was found in the CSF of patients with compared with healthy controls (epileptic patients = 2.55 ± 1.78 pmol/ml; healthy controls = 11.65 ± 7.53 pmol/ml; n = 9 for both groups, p

Of the endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have received the most study. A functional interaction between these molecules has never been described. Using mouse brain slices, we found that stimulation of metabotropic glutamate 5 receptors by 3,5-dihydroxyphenylglycine (DHPG) depressed inhibitory transmission in the striatum through selective involvement of 2-AG metabolism and stimulation of presynaptic CB1 receptors. Elevation of AEA concentrations by pharmacological or genetic inhibition of AEA degradation reduced the levels, metabolism and physiological effects of 2-AG. Exogenous AEA and the stable AEA analog methanandamide inhibited basal and DHPG-stimulated 2-AG production, confirming that AEA is responsible for the downregulation of the other eCB. AEA is an endovanilloid substance, and the stimulation of transient receptor potential vanilloid 1 (TRPV1) channels mimicked the effects of endogenous AEA on 2-AG metabolism through a previously unknown glutathione-dependent pathway. Consistently, the interaction between AEA and 2-AG was lost after pharmacological and genetic inactivation of TRPV1 channels.

Synaptic rearrangements in the peri-infarct regions are believed to contribute to the partial recovery of function that takes place after stroke. Here, we performed neurophysiological recordings from single neurons of rats with permanent occlusion of the middle cerebral artery (pMCAO) during the resolution of their neurological deficits. Our results show that complex and dynamic changes of glutamate transmission in the peri-infarct area parallel the recovery from brain infarct. We have observed that frequency and duration of spontaneous glutamate-mediated synaptic events were markedly increased in striatal neurons during the early phase of the recovery (3 days after pMCAO), due to potentiation of both NMDA (N-methyl-d-aspartate) and non-NMDA receptor-mediated transmission. In the late phase of recovery (7 days after pMCAO), glutamate transmission was still enhanced because of a selective facilitation of non-NMDA receptor-mediated transmission. Spiny projection neurons but not aspiny interneurons underwent detectable changes of synaptic excitability in the striatum following pMCAO, indicating that the process of neuronal adaptation after focal brain ischemia is cell-type-specific. Our results provide a synaptic correlate of the long-lasting brain hyperexcitability mediating recovery described with noninvasive neurophysiological approaches.

Objective: To investigate whether repetitive transcranial magnetic stimulation (rTMS) can modify spasticity.Methods: We used high-frequency (5 Hz) and low-frequency (1 Hz) rTMS protocols in 19 remitting patients with relapsing–remitting multiple sclerosis and lower limb spasticity.Results: A single session of 1 Hz rTMS over the leg primary motor cortex increased H/M amplitude ratio of the soleus H reflex, a reliable neurophysiologic measure of stretch reflex. Five hertz rTMS decreased H/M amplitude ratio of the soleus H reflex and increased corticospinal excitability. Single sessions did not induce any effect on spasticity. A significant improvement of lower limb spasticity was observed when rTMS applications were repeated during a 2-week period. Clinical improvement was long-lasting (at least 7 days after the end of treatment) when the patients underwent 5 Hz rTMS treatment during a 2-week protocol. No effect was obtained after a 2-week sham stimulation.Conclusions: Repetitive transcranial magnetic stimulation may improve spasticity in multiple sclerosis.

Restless legs syndrome (RLS)/Willis-Ekbom disease is 3-fold more prevalent in pregnant than in non-pregnant women. Symptoms are particularly strong and frequent during the third trimester of pregnancy and disappear around delivery. A pre-existing form of RLS tends to worsen during pregnancy. Women who experience RLS during pregnancy have a higher risk of symptoms in further pregnancies and of developing a primary form of RLS later in life, than women free of symptoms during pregnancy. This article reviews the literature for pregnancy-related RLS, with particular attention to its epidemiology, course, possible mechanisms, management, and the impact of symptoms.

We tested the effects of 5-Hz rTMS over the motor cortex in multiple sclerosis (MS) subjects complaining of lower urinary tract symptoms either in the filling or voiding phase. Our data show that motor cortex stimulation for five consecutive days over two weeks ameliorates the voiding phase of the micturition cycle, suggesting that enhancing corticospinal tract excitability might be useful to ameliorate detrusor contraction and/or urethral sphincter relaxation in MS patients with bladder dysfunction. Multiple Sclerosis 2007; 13: 269–271. http://msj.sagepub.com

Spreading of slow cortical rhythms into the basal ganglia (BG) is a relatively well-demonstrated phenomenon in the Parkinsonian state, both in humans and animals. Accordingly, striatal dopamine (DA) depletion, either acute or chronic, drives cortical-globus pallidus (GP) and cortical-substantia nigra pars reticulata (SNr) slow wave coherences in urethane-anesthetized rats. This paper investigates the striatal dynamics following acute DA depletion by tetrodotoxin (TTX) injection in the medial forebrain bundle (MFB) with respect to the transmission of slow cortical rhythms throughout the BG in more detail. The acute DA depletion offers the advantage of detecting electrophysiological changes irrespectively of chronically developing compensatory mechanisms. We observed that the acute blockade of the dopaminergic nigro-striatal pathway reshapes the firing rate and pattern of the different striatal neuron subtypes according to cortical activity, possibly reflecting a remodeled intrastriatal network. The observed alterations differ amongst striatal neuronal subtypes with the striatal medium spiny neurons and fast-spiking neurons being the most affected, while the tonically active neurons seem to be less affected. These acute changes might contribute to the diffusion of cortical activity to BG and the pathophysiology of Parkinson's disease (PD)., peer-reviewed

The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug-naive patients affected by temporal lobe epilepsy (TLE).We measured the levels of both AEA and the other endocannabinoid, 2-arachidonoylglycerol (2-AG), in the CSF of drug-naive patients with TLE.A significant reduction of AEA was found in the CSF of patients with compared with healthy controls (epileptic patients = 2.55 +/- 1.78 pmol/ml; healthy controls = 11.65 +/- 7.53 pmol/ml; n = 9 for both groups, p0.01). 2-AG levels, however, were not affected (epileptic patients = 209.5 +/- 146.56; healthy controls = 159.6 +/- 110.2) (n = 6 for both groups, p = 0.48).Our findings seem to be consistent with experimental evidence demonstrating a significant prevention of epileptic seizures induced by endocannabinoids in models of epilepsy. Furthermore, they support the hypothesis that AEA may be involved in its pathogenesis, suggesting a hypothetical primary impairment of the endocannabinoid system in untreated TLE. The actual role of this in vivo dysregulation still remains unclear.

Background Chronic, intermittent exposure to psychostimulant drugs results in striatal neuroadaptations leading to an increase in an array of behavioral responses on subsequent challenge days. A brain-specific striatal-enriched tyrosine phosphatase (STEP) regulates synaptic strengthening by dephosphorylating and inactivating several key synaptic proteins. This study tests the hypothesis that a substrate-trapping form of STEP will prevent the development of amphetamine-induced stereotypies. Methods A substrate-trapping STEP protein, TAT-STEP (C-S), was infused into the ventrolateral striatum on each of 5 consecutive exposure days and 1 hour before amphetamine injection. Animals were challenged to see whether sensitization to the stereotypy-producing effects of amphetamine developed. The same TAT-STEP (C-S) protein was used on acute striatal slices to determine the impact on long-term potentiation and depression. Results Infusion of TAT-STEP (C-S) blocks the increase of amphetamine-induced stereotypies when given during the 5-day period of sensitization. The TAT-STEP (C-S) has no effect if only infused on the challenge day. Treatment of acute striatal slices with TAT-STEP (C-S) blocks the induction of long-term potentiation and potentates long-term depression. Conclusions A substrate trapping form of STEP blocks the induction of amphetamine-induced neuroplasticity within the ventrolateral striatum and supports the hypothesis that STEP functions as a tonic break on synaptic strengthening.

Transient receptor potential vanilloid 1 (TRPV1) channels participate in the modulation of synaptic transmission in the periphery and in central structures. Here, we investigated the role of TRPV1 channels in the control of both excitatory and inhibitory transmission in the striatum. Pharmacological stimulation of TRPV1 channels with capsaicin (10 nM) selectively enhanced the frequency of glutamate-mediated spontaneous (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) recorded from putative striatal medium spiny neurons. Capsaicin-mediated response underwent a rapid rundown, and was no longer detected in the majority of the neurons when the concentration of the drug was in the micromolar range, possibly due to receptor desensitization. Consistently, the totality of striatal neurons responded to capsaicin (10 nM or 10 microM) after prevention of desensitization of TRPV1 channels with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA). PMA was able per se to increase sEPSC frequency. The effects of capsaicin and of PMA were absent after pharmacological or genetic inactivation of TRPV1 channels. Finally, we provided evidence for anandamide as an endovanilloid substance in the striatum, since genetic inhibition of anandamide degradation resulted in a tonic activation of TRPV1 channels modulating glutamate but not GABA release. TRPV1-mediated regulation of excitatory transmission in the striatum might be important for the final output to other basal ganglia structures, and might play a role in several physiological and pathological processes.

We tested the effects of 5-Hz repetitive transcranial magnetic stimulation (rTMS) over the motor cortex in multiple sclerosis (MS) subjects with cerebellar symptoms. rTMS improved hand dexterity in cerebellar patients ( n = 8) but not in healthy subjects ( n = 7), as detected by a significant transient reduction of the time required to complete the nine-hole pegboard task. rTMS of the motor cortex may be a useful approach to treat cerebellar impairment in MS patients.

Recent anatomical studies showed the presence of cerebellar and basal ganglia connections. It is thus conceivable that the cerebellum may influence the striatal synaptic transmission in general, and synaptic plasticity in particular.In the present neurophysiological investigation in brain slices, we studied striatal long-term depression (LTD), a crucial form of synaptic plasticity involved in motor learning after cerebellar lesions in rats.Striatal LTD was fully abolished in the left striatum of rats with right hemicerebellectomy recorded 3 and 7 days following surgery, when the motor deficits were at their peak. Fifteen days after the hemicerebellectomy, rats had partially compensated their motor deficits and high-frequency stimulation of excitatory synapses in the left striatum was able to induce a stable LTD. Striatal plasticity was conversely normal ipsilaterally to cerebellar lesions, as well as in the right and left striatum of sham-operated animals.These data show that the cerebellum controls striatal synaptic plasticity, supporting the notion that the two structures operate in conjunction during motor learning.

Rhes is a small GTP-binding protein prominently localized in the striatum. Previous findings obtained in cell culture systems demonstrated an involvement of Rhes in cAMP/PKA signalling pathway, at a level proximal to the activation of heterotrimeric G-protein complex. However, its role in the striatum has been, so far, only supposed. Here we studied the involvement of Rhes in dopaminergic signalling, by employing mice with a null mutation in the Rhes gene. We demonstrated that the absence of Rhes modulates cAMP/PKA signalling in both striatopallidal and striatonigral projection neurons by increasing Golf. protein levels and, in turn, influencing motor responses challenged by dopaminergic agonist/antagonist. Interestingly, we also show that Rhes is required for a correct dopamine-mediated GTP binding, a function mainly associated to stimulation of dopamine D2 receptors. Altogether, our results indicate that Rhes is an important modulator of dopaminergic transmission in the striatum. (C) 2007 Elsevier Inc. All rights reserved.

The ability of cannabinoids to modulate both inflammatory and degenerative neuronal damage prompted investigations on the potential benefits of such compounds in multiple sclerosis (MS) and in animal models of this disorder. Here we measured endocannabinoid levels, metabolism and binding, and physiological activities in 26 patients with MS (17 females, aged 19-43 years), 25 healthy controls and in mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. Our results show that MS and EAE are associated with significant alterations of the endocannabinoid system. We found that anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), was increased in the CSF of relapsing MS patients. AEA concentrations were also higher in peripheral lymphocytes of these patients, an effect associated with increased synthesis and reduced degradation of this endocannabinoid. Increased synthesis, reduced degradation, and increased levels of AEA were also detected in the brains of EAE mice in the acute phase of the disease, possibly accounting for its anti-excitotoxic action in this disorder. Accordingly, neurophysiological recordings from single neurons confirmed that excitatory transmission in EAE slices is inhibited by CB1 receptor activation, while inhibitory transmission is not. Our study suggests that targeting the endocannabinoid system might be useful for the treatment of MS.

Dopamine D2receptor (D2DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D2receptors in this brain area are essentially obscure. We have studied the physiological responses of the D2DR stimulations in mice lacking the brain cytoplasmic RNA BC1, a small noncoding dendritically localized RNA that is supposed to play a role in mRNA translation. We show that the efficiency of D2-mediated transmission regulating striatal GABA synapses is under the control of BC1 RNA, through a negative influence on D2receptor protein level affecting the functional pool of receptors. Ablation of the BC1 gene did not result in widespread dysregulation of synaptic transmission, because the sensitivity of cannabinoid CB1receptors was intact in the striatum of BC1 knock-out (KO) mice despite D2and CB1receptors mediated similar electrophysiological actions. Interestingly, the fragile X mental retardation protein FMRP, one of the multiple BC1 partners, is not involved in the BC1 effects on the D2-mediated transmission. Because D2DR mRNA is apparently equally translated in the BC1-KO and wild-type mice, whereas the protein level is higher in BC1-KO mice, we suggest that BC1 RNA controls D2DR indirectly, probably regulating translation of molecules involved in D2DR turnover and/or stability.

Synaptic transmission in the striatum is regulated by metabotropic glutamate (mGlu) receptors through pre- and postsynaptic mechanisms. We investigated the involvement of mGlu 1 and 5 receptors in the control of both excitatory and inhibitory transmission in the striatum. The mGlu 1 and 5 receptor agonist 3,5-DHPG failed to affect glutamate transmission, while it caused a biphasic effect on GABA transmission, characterized by early increase and late decrease in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from striatal principal neurons. Both mGlu 1 and 5 receptors were involved in the early response to 3,5-DHPG, through membrane depolarization of striatal GABAergic interneurons and action potential generation. The 3,5-DHPG-mediated late depression of inhibitory inputs to striatal principal neurons was conversely secondary to mGlu 5 receptor activation and subsequent endocannabinoid release. In conclusion, we have identified an mGlu-dependent mechanism of GABA transmission regulation of potential relevance for physiological neuronal activity.

Background and Purpose— The possible neuroprotective effects of classic and new antiepileptic drugs on the electrophysiological changes induced by in vitro ischemia on striatal neurons were investigated. In particular, the aim of the study was to correlate the putative neuroprotective effects with the action of these drugs on fast sodium (Na + ) and high-voltage–activated (HVA) calcium (Ca 2+ ) currents. Methods— Extracellular field potentials were recorded from rat corticostriatal brain-slice preparations. In vitro ischemia was delivered by switching to an artificial cerebrospinal fluid solution in which glucose and oxygen were omitted. Na + and HVA Ca 2+ currents were analyzed by whole-cell patch-clamp recordings from acutely isolated rat striatal neurons. Excitatory postsynaptic potential was measured following synaptic stimulation in corticostriatal slices by sharp intracellular microelectrodes. Results— Neuroprotection against in vitro ischemia was observed in slices treated with carbamazepine (CBZ), valproic acid (VPA), and topiramate (TPM), whereas it was not achieved by using levetiracetam (LEV). Fast Na + conductances were inhibited by CBZ and TPM, whereas VPA and LEV showed no effect. HVA Ca 2+ conductances were reduced by CBZ, TPM, and LEV. VPA had no effect on this current. All antiepileptic drugs induced a small reduction of excitatory postsynaptic potential amplitude at concentrations higher than 100 μm without changes of paired-pulse facilitation. Conclusions— The concomitant inhibition of fast Na + and HVA Ca 2+ conductances is critically important for the neuroprotection, whereas the presynaptic inhibition on glutamate transmission does not seem to play a major role.

Decreased activity of mitochondrial complex I and II is implicated in the pathophysiology of progressive supranuclear palsy (PSP) and Huntington's disease (HD), respectively. Both disorders preferentially affect the nucleus striatum, a brain area particularly vulnerable to excitotoxic damage. To gain insights into the pathophysiology of neuronal degeneration during PSP and HD, here we studied the possible interplay between excitatory transmission and mitochondrial complex I and II inhibition in the development of striatal damage. By using in vitro neurophysiological recordings and cell swelling measures in corticostriatal slices, we found that stimulation of NMDA receptors significantly contributed to the neurotoxic effects of 3-nitropropionic acid (3-NP) but not of rotenone, selective inhibitors of mitochondrial complex II and I, respectively. We also found that blockade of a subset of NMDA receptors containing the NR2B subunit was sufficient to protect the striatum from the injurious effects of 3-NP, an effect unrelated to the prevention of membrane excitation by NMDA receptor stimulation. Pharmacological inhibition of dopamine receptors, conversely, failed to modulate both rotenone- and 3-NP-induced neuronal damage. Our results indicate that the cellular mechanisms leading to striatal neuronal death are different following inhibition of distinct mitochondrial complexes of the respiratory chain, implying that neuroprotective strategies in PSP and HD must significantly differ.

Hemiballism (HB) is a quite rare disorder, generally secondary to stroke, neoplasms or demyelinating plaques, classically considered as almost pathognomonic of a lesion in the subthalamic nucleus (STN). This alteration causes involuntary movements in the chorea-ballism spectrum. One theory is that the output nuclei of the basal ganglia are overinhibited in HB, while little is known about the physiological state of the striatum, the major input structure of the basal ganglia. In the present study, we recorded spontaneous and miniature excitatory and inhibitory postsynaptic currents (sEPSCs, mEPSCs, sIPSCs, mIPSCs) from projection neurons of the striatum of experimental HB. We found a selective reduction of striatal sEPSC and mEPSC frequency following chemical lesion of the STN of the rat, suggesting that reduced synaptic excitation of the input structure of the basal ganglia represents a physiological correlate of HB.

Background The advanced stages of addiction are characterized by compulsive drug-seeking and drug-taking behaviors despite the loss of the hedonic effect of drug consumption. A pathology of habit forming systems might underlie these features of addiction. Methods We have compared use-dependent plasticity of corticostriatal synapses in saline- and cocaine-treated rats by means of single neuron electrophysiological recordings. Results High-frequency stimulation of cortical afferents induced long-term potentiation (LTP) of corticostriatal synapses in treated and untreated animals. Saline- and acute–cocaine-treated rats, however, showed synaptic depotentiation in response to subsequent low-frequency stimulation of the same pathway, whereas chronic cocaine-treated animals were refractory to this process. Depotentiation was also absent in control slices bathed with cocaine, dopamine, or with the D1 receptor agonist SKF38393. The effect of cocaine on depotentiation was prevented by D1 but not D2 dopamine receptor antagonists and was mimicked by pharmacological inhibition of cyclin-dependent kinase 5, to enhance D1-receptor–associated intracellular signaling. Conclusions These results provide the first evidence that cocaine blocks the reversal of LTP in brain circuits. This alteration might be important for the persistence of addictive behavior despite efforts to abstain.

Background One of the earliest neurochemical alterations observed in both Huntington’s disease (HD) patients and HD animal models is the dysregulation of the endocannabinoid system, an alteration that precedes the development of identifiable striatal neuropathology. How this alteration impacts striatal synaptic transmission is unknown. Methods We measured the effects of cannabinoid receptor stimulation on γ-aminobutyric acid (GABA)-ergic synaptic currents recorded from striatal neurons of R6/2 HD mice in the early phase of their disease. Results The sensitivity of striatal GABA synapses to cannabinoid receptor stimulation is severely impaired in R6/2 HD mice. In particular, whereas in control animals activation of cannabinoid CB1 receptors results in a significant inhibition of both evoked and spontaneous GABA-mediated synaptic events by a presynaptic mechanism, in R6/2 mice this treatment fails to reduce GABA currents but causes, in contrast, a slight increase of spontaneous inhibitory postsynaptic currents (sIPSCs). Conclusions Experimental HD was also associated with enhanced frequency of sIPSCs, a result consistent with the conclusion that loss of cannabinoid-mediated control of GABA transmission might contribute to hyperactivity of GABA synapses in the striatum of HD mice. Accordingly, spontaneous excitatory postsynaptic currents, which were not upregulated in R6/2 mice, were still sensitive to cannabinoid receptor stimulation.