Role of adenosine in the antiepileptic effects of deep brain stimulation

Despite the effectiveness of anterior thalamic nucleus (AN) deep brain stimulation (DBS) for the treatment of epilepsy, mechanisms responsible for the antiepileptic effects of this therapy remain elusive. As adenosine modulates neuronal excitability and seizure activity in animal models, we hypothesized that this nucleoside could be one of the substrates involved in the effects of AN DBS. We applied 5 days of stimulation to rats rendered chronically epileptic by pilocarpine injections and recorded epileptiforrn activity in hippocampal slices. We found that slices from animals given DBS had reduced hippocampal excitability and were less susceptible to develop ictal activity. in live animals, AN DBS significantly increased adenosine levels in the hippocampus as measured by microdialysis. the reduced excitability of DBS in vitro was completely abolished in animals pre-treated with A1 receptor antagonists and was strongly potentiated by A1 receptor agonists. We conclude that some of the antiepileptic effects of DBS may be mediated by adenosine.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)AFIP (Associacao Fundo de Incentivo a Pesquisa)Univ Fed Sao Joao del Rei, Lab Neurociencia Expt & Computac, Sao Joao Del Rei, BrazilUniversidade Federal de São Paulo, Disciplina Neurofisiol, São Paulo, BrazilCtr Addict & Mental Hlth, Behav Neurobiol Lab, Toronto, ON, CanadaUniv Toronto, Toronto Western Hosp, Div Neurosurg, Toronto, ON M5T 2S8, CanadaUniversidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Disciplina Neurol Expt, São Paulo, BrazilUniversidade Federal de São Paulo, Disciplina Neurofisiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Disciplina Neurol Expt, São Paulo, BrazilFAPESP: 2011150680-2FAPESP: 50950-2Web of Scienc

Deep brain stimulation of the subthalamic nucleus preferentially alters the translational profile of striatopallidal neurons in an animal model of Parkinson’s disease

Deep brain stimulation targeting the subthalamic nucleus (STN-DBS) is an effective surgical treatment for the motor symptoms of Parkinson’s disease (PD), the precise neuronal mechanisms of which both at molecular and network levels remain a topic of debate. Here we employ two transgenic mouse lines, combining translating ribosomal affinity purification (TRAP) with bacterial artificial chromosome expression (Bac), to selectively identify changes in translational gene expression in either Drd1a-expressing striatonigral or Drd2-expressing striatopallidal medium spiny neurons (MSNs) of the striatum following STN-DBS. 6-hydroxydopamine lesioned mice received either 5 days stimulation via a DBS electrode implanted in the ipsilateral STN or 5 days sham treatment (no stimulation). Striatal polyribosomal RNA was selectively purified from either Drd2 or Drd1a MSNs using the TRAP method and gene expression profiling performed. We identified 8 significantly altered genes in Drd2 MSNs (Vps33b, Ppp1r3c, Mapk4, Sorcs2, Neto1, Abca1, Penk1 and Gapdh) and 2 overlapping genes in Drd1a MSNs (Penk1 and Ppp1r3c) implicated in the molecular mechanisms of STN-DBS. A detailed functional analysis, using a further 728 probes implicated in STN-DBS, suggested an increased ability to receive excitation (mediated by increased dendritic spines, increased calcium influx and enhanced excitatory post synaptic potentials) accompanied by processes that would hamper the initiation of action potentials, transport of neurotransmitters from soma to axon terminals and vesicular release in Drd2-expressing MSNs. Finally, changes in expression of several genes involved in apoptosis as well as cholesterol and fatty acid metabolism were also identified. This increased understanding of the molecular mechanisms induced by STN-DBS may reveal novel targets for future non-surgical therapies for PD

Temporal alignment of electrocorticographic recordings for upper limb movement

The detection of movement-related components of the brain activity is useful in the design of brain machine interfaces. A common approach is to classify the brain activity into a number of templates or states. To find these templates, the neural responses are averaged over each movement task. For averaging to be effective, one must assume that the neural components occur at identical times over repeated trials. However, complex arm movements such as reaching and grasping are prone to cross-trial variability due to the way movements are performed. Typically initiation time, duration of movement and movement speed are variable even as a subject tries to reproduce the same task identically across trials. Therefore, movement-related neural activity will tend to occur at different times across each trial. Due to this mismatch, the averaging of neural activity will not bring into salience movement-related components. To address this problem, we present a method of alignment that accounts for the variabilities in the way the movements are conducted. In this study, arm speed was used to align neural activity. Four subjects had electrocorticographic (ECoG) electrodes implanted over their primary motor cortex and were asked to perform reaching and retrieving tasks using the upper limb contralateral to the site of electrode implantation. The arm speeds were aligned using a nonlinear transformation of the temporal axes resulting in averaged spectrograms with superior visualization of movement-related neural activity when compared to averaging without alignment

Replacement of asymmetric synaptic profiles in the molecular layer of dentate gyrus following cycloheximide in the pilocarpine model in rats.

Mossy fiber sprouting is among the best-studied forms of post-lesional synaptic plasticity and is regarded by many as contributory to seizures in both humans and animal models of epilepsy. It is not known whether mossy fiber sprouting increases the number of synapses in the molecular layer or merely replaces lost contacts. Using the pilocarpine model of status epilepticus to induce mossy fiber sprouting, and cycloheximide to block this sprouting, we evaluated at the ultrastructural level the number and type of asymmetric synaptic contacts in the molecular layer of the dentate gyrus. As expected, whereas pilocarpine-treated rats had dense silver grain deposits in the inner molecular layer (reflecting mossy fiber sprouting), pilocarpine+cycloheximide-treated animals did not differ from controls. Both groups of treated rats (Pilo group and CHX+Pilo group) had reduced density of asymmetric synaptic profiles (putative excitatory synaptic contacts), which was greater for cycloheximide-treated animals. For both treated groups the loss of excitatory synaptic contacts was even greater in the outer molecular layer than in the best studied inner molecular layer (in which mossy fiber sprouting occurs). These results indicate that mossy fiber sprouting tends to replace lost synaptic contacts rather than increase the absolute number of contacts. We speculate that the overall result is more consistent with restored rather than with increased excitability