Faculty Bibliography

In catamenial epilepsy, seizures exhibit a cyclic pattern that parallels the menstrual cycle. Many studies suggest that catamenial seizures are caused by fluctuations in gonadal hormones during the menstrual cycle, but this has been difficult to study in rodent models of epilepsy because the ovarian cycle in rodents, called the estrous cycle, is disrupted by severe seizures. Thus, when epilepsy is severe, estrous cycles become irregular or stop. Therefore, we modified kainic acid (KA)- and pilocarpine-induced status epilepticus (SE) models of epilepsy so that seizures were rare for the first months after SE, and conducted video-EEG during this time. The results showed that interictal spikes (IIS) occurred intermittently. All rats with regular 4-day estrous cycles had IIS that waxed and waned with the estrous cycle. The association between the estrous cycle and IIS was strong: if the estrous cycles became irregular transiently, IIS frequency also became irregular, and when the estrous cycle resumed its 4-day pattern, IIS frequency did also. Furthermore, when rats were ovariectomized, or males were recorded, IIS frequency did not show a 4-day pattern. Systemic administration of an estrogen receptor antagonist stopped the estrous cycle transiently, accompanied by transient irregularity of the IIS pattern. Eventually all animals developed severe, frequent seizures and at that time both the estrous cycle and the IIS became irregular. We conclude that the estrous cycle entrains IIS in the modified KA and pilocarpine SE models of epilepsy. The data suggest that the ovarian cycle influences more aspects of epilepsy than seizure susceptibility.

Orthostatic hypotension (OH) is frequent in patients with Parkinson's disease (PD) and can occur with or without symptoms. Pharmacological treatments are effective, but often exacerbate supine hypertension. Guidelines exist for the diagnosis, but not for the treatment of OH. We examined the relationship between blood pressure (BP) and symptoms in a cohort of PD patients with the goal of identifying a hemodynamic target to guide treatment. We measured BP supine and upright (tilt or active standing) and identified the presence or absence of symptomatic OH by using a validated patient-reported outcome questionnaire in 210 patients with PD. We evaluated the usefulness of the 20/10 and 30/15 mmHg diagnostic criteria (systolic/diastolic) to identify symptomatic OH. Fifty percent of the PD patient cohort met criteria for the 20/10 fall and 30% for the 30/15 BP fall. Among the patients who met either OH criteria, the percentage of those with symptoms was small (33% of those with 20/10 and 44% of those with 30/15 mmHg; 16% and 13%, respectively, overall). Symptomatic OH was associated with an upright mean BP below 75 mmHg. A mean standing BP <75 mmHg had a sensitivity of 97% and a specificity of 98% for detecting symptomatic OH. Although the prevalence of OH in PD is high, not all patients have symptoms of organ hypoperfusion. A mean standing BP below 75 mmHg appears to be a useful benchmark when deciding whether the benefits of initiating pharmacological treatment of OH outweigh the risks of exacerbating supine hypertension. (c) 2015 International Parkinson and Movement Disorder Society.

Cystinuria is a genetic disease marked by recurrent kidney stone formation, usually at a young age. It frequently leads to chronic kidney disease. Treatment options for cystinuria have been limited despite comprehensive understanding of its genetic pathophysiology. Currently available therapies suffer from either poor clinical adherence to the regimen or potentially serious adverse effects. Recently, we employed atomic force miscopy (AFM) to identify L-cystine dimethylester (CDME) as an effective molecular imposter of L-cystine, capable of inhibiting crystal growth in vitro. More recently, we demonstrated CDME's efficacy in inhibiting L-cystine crystal growth in vivo utilizing a murine model of cystinuria. The application of AFM to discover inhibitors of crystal growth through structural mimicry suggests a novel approach to preventing and treating crystal diseases.

Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing.

OBJECTIVE: We examined whether individual neuronal architecture obtained from the brain connectome can be used to estimate the surgical success of anterior temporal lobectomy (ATL) in patients with temporal lobe epilepsy (TLE). METHODS: We retrospectively studied 35 consecutive patients with TLE who underwent ATL. The structural brain connectome was reconstructed from all patients using presurgical diffusion MRI. Network links in patients were standardized as Z scores based on connectomes reconstructed from healthy controls. The topography of abnormalities in linkwise elements of the connectome was assessed on subnetworks linking ipsilateral temporal with extratemporal regions. Predictive models were constructed based on the individual prevalence of linkwise Z scores >2 and based on presurgical clinical data. RESULTS: Patients were more likely to achieve postsurgical seizure freedom if they exhibited fewer abnormalities within a subnetwork composed of the ipsilateral hippocampus, amygdala, thalamus, superior frontal region, lateral temporal gyri, insula, orbitofrontal cortex, cingulate, and lateral occipital gyrus. Seizure-free surgical outcome was predicted by neural architecture alone with 90% specificity (83% accuracy), and by neural architecture combined with clinical data with 94% specificity (88% accuracy). CONCLUSIONS: Individual variations in connectome topography, combined with presurgical clinical data, may be used as biomarkers to better estimate surgical outcomes in patients with TLE.

Reactive oxygen species (ROS) are believed to be important mediators of muscle atrophy and weakness in aging and many degenerative conditions. However, the mechanisms and physiological processes specifically affected by elevated ROS in neuromuscular units that contribute to muscle weakness during aging are not well defined. Here we investigate the effects of chronic oxidative stress on neurotransmission and excitation-contraction (EC) coupling mechanisms in the levator auris longus (LAL) muscle from young (4-8 months) and old (22-28 months) wild type mice and young adult Sod1-/- mice. The frequency of spontaneous neurotransmitter release and the amplitude of evoked neurotransmitter release in young Sod1-/- and old wild type LAL neuromuscular junctions were significantly reduced from the young wild type values, and those declines were mirrored by decreases in synaptic vesicle pool size. Presynaptic cytosolic calcium concentration and mitochondrial calcium uptake amplitudes showed substantial increases in stimulated young Sod1-/- and old axon terminals. Surprisingly, LAL muscle fibers from old mice showed a greater excitability than fibers from either young wild type or young Sod1-/- LAL muscle fibers. Both evoked excitatory junction potential (EJP) and spontaneous mini EJP amplitudes were considerably higher in LAL muscles from old mice than in fibers from young Sod1-/- LAL muscle. Despite a greater excitability, sarcoplasmic calcium influx in both old wild type and young Sod1-/- LAL muscle fibers was significantly smaller. Sarcoplasmic reticulum calcium levels were also smaller in both mice, but the difference was not statistically significant in muscle fibers from old wild type mice. The protein ratio of triad calcium channels - RyR1/DHPR was not different in all groups. However, fibers from both Sod1-/- and old mice had substantially elevated levels of protein carbonylation and S-nitrosylation modifications. Overall, our results suggest that young Sod1-/- recapitulate many neuromuscular and muscle fiber changes seen in old mice. We also conclude that muscle weakness in old mice might in part be driven by ROS mediated EC uncoupling, while both EC uncoupling and reduced neurotransmitter release contribute to muscle weakness in Sod1-/- mice.

To understand how function arises from the interactions between neurons, it is necessary to use methods that allow the monitoring of brain activity at the single-neuron, single-spike level and the targeted manipulation of the diverse neuron types selectively in a closed-loop manner. Large-scale recordings of neuronal spiking combined with optogenetic perturbation of identified individual neurons has emerged as a suitable method for such tasks in behaving animals. To fully exploit the potential power of these methods, multiple steps of technical innovation are needed. We highlight the current state of the art in electrophysiological recording methods, combined with optogenetics, and discuss directions for progress. In addition, we point to areas where rapid development is in progress and discuss topics where near-term improvements are possible and needed.

Synapses are plastic and can be modified by changes in spike timing. Whereas most studies of long-term synaptic plasticity focus on excitation, inhibitory plasticity may be critical for controlling information processing, memory storage, and overall excitability in neural circuits. Here we examine spike-timing-dependent plasticity (STDP) of inhibitory synapses onto layer 5 neurons in slices of mouse auditory cortex, together with concomitant STDP of excitatory synapses. Pairing pre- and postsynaptic spikes potentiated inhibitory inputs irrespective of precise temporal order within approximately 10 ms. This was in contrast to excitatory inputs, which displayed an asymmetrical STDP time window. These combined synaptic modifications both required NMDA receptor activation and adjusted the excitatory-inhibitory ratio of events paired with postsynaptic spiking. Finally, subthreshold events became suprathreshold, and the time window between excitation and inhibition became more precise. These findings demonstrate that cortical inhibitory plasticity requires interactions with co-activated excitatory synapses to properly regulate excitatory-inhibitory balance.