Involvement of the hippocampus and medial entorhinal cortex in bridging discontinuous events

The medial entorhinal cortex (MEC) projects directly to the hippocampus. It is considered the major contributor of spatial information to the hippocampal place cells (1-3). However, it remains unclear to what extent MEC spatial firing is necessary for memory-guided behavior. We found that complete single or double bilateral lesions to the MEC and the hippocampus impaired rats in the delayed alternation task. Single lesioned rats partially improved their behavioral performance in delay trials across time. However, physiological analysis of CA1 cells in the MEC lesioned rats indicated less precision in firing, as well as less discrimination between left and right trials. Double lesioned rats did not present any behavioral improvement throughout trials, but in fact exhibited perseveration. These results could indicate that single lesions of either structure disrupt the function of the entorhino-hippocampal loop. Over time residual neurons of the intact structure are sufficient to compensate for the communication with the prefrontal cortex, as supported by partial behavioral recoveries. Double lesioned animals, however, are prevented from improving in memory related tasks

Botulinum toxin therapy in Parkinson disease-related lower limb dystonia. An 8 year retrospective review

Background: Lower extremity dystonia (LED) is a frequent complication of Parkinson disease (PD). Treatment with botulinum neurotoxinA (BoNTA) over 8 years was retrospectively reviewed.Cases14 patients with LED received an average of 3.86 injections (1–8). Mean interval was 40 weeks (median of 25). Average dose was 182 units. Injections were well-tolerated. Using a 6 point scale, there was an average of 3.37 point improvement in disability after each session, with average duration of 28.56 weeks (median 11 weeks). After mean follow-up of 101 weeks, disabling dystonia was not present in 11 of 14 patients. Conclusions: Botulinum toxin is safe and effective in PD related LED. Good response to the first two injection sessions was significantly associated with greater likelihood of long-term response. Assertive BoNTA dosing may lead to sustained remission of symptoms. As natural history of LED in PD has not been reported, prospective placebo-controlled studies are needed

Astrocyte and Neuronal Panx1 Support Long-Term Reference Memory in Mice

Pannexin 1 (Panx1) is an ubiquitously expressed protein that forms plasma membrane channels permeable to anions and moderate-sized signaling molecules (e.g., ATP, glutamate). In the nervous system, activation of Panx1 channels has been extensively shown to contribute to distinct neurological disorders (epilepsy, chronic pain, migraine, neuroAIDS, etc.), but knowledge of the extent to which these channels have a physiological role remains restricted to three studies supporting their involvement in hippocampus dependent learning. Given that Panx1 channels may provide an important mechanism for activity-dependent neuron-glia interaction, we used Panx1 transgenic mice with global and cell-type specific deletions of Panx1 to interrogate their participation in working and reference memory. Using the eight-arm radial maze, we show that long-term spatial reference memory, but not spatial working memory, is deficient in Panx1-null mice and that both astrocyte and neuronal Panx1 contribute to the consolidation of long-term spatial memory. Field potential recordings in hippocampal slices of Panx1-null mice revealed an attenuation of both long-term potentiation (LTP) of synaptic strength and long-term depression (LTD) at Schaffer collateral-CA1 synapses without alterations of basal synaptic transmission or pre-synaptic paired-pulse facilitation. Our results implicate both neuronal and astrocyte Panx1 channels as critical players for the development and maintenance of long-term spatial reference memory in mice

Novel Neurosteroid Pregnanolone Pyroglutamate Suppresses Neurotoxicity Syndrome Induced by Tetramethylenedisulfotetramine but Is Ineffective in a Rodent Model of Infantile Spasms

BACKGROUND: Neurosteroids are investigated as effective antidotes for the poisoning induced by tetramethylenedisulfotetramine (TMDT) as well as treatments for epileptic spasms during infancy. Both these conditions are quite resistant to pharmacotherapy; thus, a search for new treatments is warranted. METHODS: In this study, we determined the efficacy of two novel neurosteroids, pregnanolone glutamate (PAG) and pregnanolone pyroglutamate (PPG), and tested these drugs in doses of 1-10 mg/kg (ip) against the TMDT syndrome and in our rodent model of infantile spasms. RESULTS: Only PPG in doses 5 and 10 mg/kg suppressed the severity of the TMDT syndrome and TMDT-induced lethality, while the 1 mg/kg dose was without an effect. Interestingly, the 1 mg/kg dose of PPG in combination with 1 mg/kg of diazepam was also effective against TMDT poisoning. Neither PAG nor PPG were effective against experimental spasms in the N-methyl-D-aspartate (NMDA)-triggered model of infantile spasms. CONCLUSIONS: While evidence suggests that PAG can act through multiple actions which include allosteric inhibition of NMDA-induced and glycine receptor-evoked currents as well as augmentation of ɣ-aminobutyric acid subtype A (GABAA) receptor-induced currents, the agent appears to neither have the appropriate mechanistic signature for activity in the infantile spasm model, nor the adequate potency, relative to PPG, for ameliorating the TMDT syndrome. The full mechanisms of action of PPG, which may become a potent TMDT antidote either alone or in combination with diazepam are yet unknown and thus require further investigation