Parvalbumin (PV)-expressing interneurons exert powerful inhibitory effects on the normal cortical network; thus optogenetic activation of PV interneurons may also possess antiepileptic properties. To investigate this possibility we expressed channelrhodopsin 2 in PV interneurons by locally injecting the Cre-dependent viral vector AAV2/1-EF1a-DIO-ChETA-EYFP into the S1 barrel cortex of PV-Cre mice. Approximately 3-4 wk later recurrent electrographic seizures were evoked by local application of the chemoconvulsant 4-aminopyridine (4-AP); the ECoG and unit activity were monitored with extracellular silicone electrodes; and PV interneurons were activated optogenetically during the ictal and interictal phases. Five- to ten-second optogenetic activation of PV interneurons applied during electrographic seizures (ictal phase) terminated 33.7% of electrographic seizures compared with only 6% during sham stimulation, and the average electrographic seizure duration shortened by 38.7 ± 34.2% compared with sham stimulation. In contrast, interictal optogenetic activation of PV interneurons showed powerful and robust ictogenic effects. Approximately 60% of interictal optogenetic stimuli resulted in electrographic seizure initiation. Single-unit recordings revealed that presumptive PV-expressing interneurons markedly increased their firing during optogenetic stimulation, while many presumptive excitatory pyramidal neurons showed a biphasic response, with initial suppression of firing during the optogenetic pulse followed by a synchronized rebound increase in firing at the end of the laser pulse. Our findings indicated that ictal activation of PV-expressing interneurons possesses antiepileptic properties probably due to suppression of firing in pyramidal neurons during the laser pulse. However, in addition interictal activation of PV-expressing interneurons possesses powerful ictogenic properties, probably due to synchronized postinhibition rebound firing of pyramidal neurons.

We have previously reported that a single injection of an ultra-low dose of delta-9-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) protected the brain from pentylenentetrazole (PTZ)-induced cognitive deficits when applied 1-7 days before or 1-3 days after the insult. In the present study we expanded the protective profile of THC by showing that it protected mice from cognitive deficits that were induced by a variety of other neuronal insults, including pentobarbital-induced deep anesthesia, repeated treatment with 3,4 methylenedioxymethamphetamine (MDMA; "ecstasy") and exposure to carbon monoxide. The protective effect of THC lasted for at least 7 weeks. The same ultra-low dose of THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that produce the known acute effects of the drug in mice) induced long-lasting (7 weeks) modifications of extracellular signal-regulated kinase (ERK) activity in the hippocampus, frontal cortex and cerebellum of the mice. The alterations in ERK activity paralleled changes in its activating enzyme MEK and its inactivating enzyme MKP-1. Furthermore, a single treatment with the low dose of THC elevated the level of pCREB (phosphorylated cAMP response element-binding protein) in the hippocampus and the level of BDNF (brain-derived neurotrophic factor) in the frontal cortex. These long-lasting effects indicate that a single treatment with an ultra-low dose of THC can modify brain plasticity and induce long-term behavioral and developmental effects in the brain.

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Background PD is a common neurodegenerative disease primarily affecting the cortico–basal ganglia loop. Objective To investigate whether chemogenetic‐mediated neuromodulation of various nuclei and pathways can counterbalance basal ganglia network abnormalities and improve motor disability in experimental PD. Methods Experimental PD was induced by stereotactic injection of 6‐OHDA to the medial forebrain bundle. Designer receptors exclusively activated by designer drugs were expressed in different basal ganglia nuclei by stereotactic injections of adeno‐associated viral vectors. We compared motor performance, monitored by the open‐field and rotarod tests, after random and blinded application of either normal saline or the synthetic receptor activator, clozapine‐N‐oxide. Results Motor performance, as measured by movement velocity, rotations, and rotarod scores, were significantly improved in PD mice by enhancing the activity of the GPe with Gq custom receptors and by reducing basal ganglia output activity, targeting the output nuclei GPi and SNr with Gi custom receptors. Conclusion Our findings support the hypothesis that enhanced inhibitory output activity of the basal ganglia complex underlie motor signs in PD, and point to the therapeutic potential of chemogenetic based treatments in PD patients. © 2018 International Parkinson and Movement Disorder Society

Epilepsy affects over 70 million people worldwide and 30% of patients' seizures cannot be controlled with medications, motivating the development of alternative therapies such as electrical stimulation. Current stimulation strategies attempt to stop seizures after they start, but none aim to prevent seizures altogether. Preventing seizures requires knowing when the brain is entering a preictal state (i.e., approaching seizure onset). Here we show that such preictal activity can be detected by an informative neural signal that progressively and monotonically changes as the brain approaches a seizure event. Specifically, we use local field potentials (LFP) from a rat model of epilepsy to develop an innovative measure of signal novelty relative to nonseizure activity, that shows the presence of progressive neural dynamics in an ultra broad band (4 Hz -5 kHz). The measure is extracted from functional connectivity features computed from the LFPs which are used as an input to a one-class Support Vector Machine (SVM). The SVM outputs a scalar signal which quantifies how novel the current activity looks relative to baseline (non-seizure) activity and shows a progression towards seizure onset minutes ahead of time. The use of ultra broad band multivariate features into the SVM results in a novelty signal that has a significantly higher slope in the progression to seizure onset when compared to using power in conventional frequency bands (4 -500 Hz) on individual channels as input features to the SVM. Functional connectivity in conjunction with the SVM is a strategy that generates a new measurement of novelty that can be used by closed-loop systems for seizure forecasting and prevention.