Adenosine A_(2A)receptor blockade attenuates excitotoxicity in rat striatal medium spiny neurons during an ischemic-like insult

During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.

Generating a reporter mouse line marking medium spiny neurons in the developing striatum driven by Arpp21 cis-regulatory elements

The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, 2008). Most cells in the striatum are GABAergic, including a large population (90%-95%) of medium spiny neurons (MSNs) and a small population of interneurons.

Homeobox Gene Six3 is Required for the Differentiation of D2-Type Medium Spiny Neurons

Medium spiny neurons(MSNs)in the striatum,which can be divided into D1 and D2 MSNs,originate from the lateral ganglionic eminence(LGE).Previously,we reported that Six3 is a downstream target of Sp8/Sp9 in the transcriptional regulatory cascade of D2 MSN development and that conditionally knocking out Six3 leads to a severe loss of D2 MSNs.Here,we showed that Six3 mainly functions in D2 MSN precursor cells and gradually loses its function as D2 MSNs mature.Conditional deletion of Six3 had little effect on cell proliferation but blocked the differentiation of D2 MSN precursor cells.In addition,conditional overexpression of Six3 promoted the differentiation of precursor cells in the LGE.We measured an increase of apoptosis in the postnatal striatum of conditional Six3-knockout mice.This suggests that,in the absence of Six3,abnormally differentiated D2 MSNs are eliminated by programmed cell death.These results further identify Six3 as an important regulatory element during D2 MSN differentiation.

Therapeutic advances in neural regeneration for Huntington’s disease

Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.

The adjustment of γ-aminobutyric acid_A tonic subunits in Huntington＇s disease：from transcription to translation to synaptic levels into the neostriatum

γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6,β3,δ,or ρ1-3 subunits,they are located at perisynaptic and/or in extrasynaptic regions.The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation.On this basis,GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington＇s disease.Huntington＇s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein.For experimental studies of Huntington＇s disease mouse models have been developed,such as R6/1,R6/2,Hdh Q92,Hdh Q150,as well as YAC128.In all of them,some key experimental reports are focused on neostriatum.The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures,its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively,they display strong expression of many types of GABAA receptors,including tonic subunits.The studies about of GABAA tonic subunits and Huntington＇s disease into the neostriatum are rising in recent years,suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition,a hallmark of Huntington＇s disease.

Single Exposure to Cocaine Impairs Reinforcement Learning by Potentiating the Activity of Neurons in the Direct Striatal Pathway in Mice

Plasticity in the glutamatergic synapses on striatal medium spiny neurons(MSNs)is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse.Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment.In the present work,we found that the negative reinforcement learning,escaping mild foot-shocks by correct nose-poking,was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice.Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1(D1)receptor(D1-MSNs).However,24 h after the cocaine exposure,the potentiation required for reinforcement learning was disrupted.Specific manipulation of the activity of striatal D1-MSNs in D1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal D1-cre mice,but inhibition of these neurons reversed the reinforcement learning impairment induced by cocaine.The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.

Parkinson’s disease and translational research

Parkinson's disease(PD)is diagnosed when patients exhibit bradykinesia with tremor and/or rigidity,and when these symptoms respond to dopaminergic medications.Yet in the last years there was a greater recognition of additional aspects of the disease including non-motor symptoms and prodromal states with associated pathology in various regions of the nervous system.In this review we discuss current concepts of two major alterations found during the course of the disease:cytoplasmic aggregates of the protein a-synuclein and the degeneration of dopaminergic neurons.We provide an overview of new approaches in this field based on current concepts and latest literature.In many areas,translational research on PD has advanced the understanding of the disease but there is still a need for more effective therapeutic options based on the insights into the basic biological phenomena.