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Neurons and glial cells are endowed with membranes that express a rich repertoire of ion channels, transporters, and receptors. The constant flux of ions across the neuronal and glial membranes results in voltage fluctuations that can be recorded from the extracellular matrix. The high frequency components of this voltage signal contain information about the spiking activity, reflecting the output from the neurons surrounding the recording location. The low frequency components of the signal, referred to as the local field potential (LFP), have been traditionally thought to provide information about the synaptic inputs that impinge on the large dendritic trees of various neurons. In this review, we discuss recent computational and experimental studies pointing to a critical role of several active dendritic mechanisms that can influence the genesis and the location-dependent spectro-temporal dynamics of LFPs, spanning different brain regions. We strongly emphasize the need to account for the several fast and slow dendritic events and associated active mechanisms — including gradients in their expression profiles, inter- and intra-cellular spatio-temporal interactions spanning neurons and glia, heterogeneities and degeneracy across scales, neuromodulatory influences, and activitydependent plasticity — towards gaining important insights about the origins of LFP under different behavioral states in health and disease. We provide simple but essential guidelines on how to model LFPs taking into account these dendritic mechanisms, with detailed methodology on how to account for various heterogeneities and electrophysiological properties of neurons and synapses while studying LFPs.

Introduction: GDF11 is a pleiotropic circulating blood factor and member of the transforming growth factor β (TGFβ) superfamily. In animal models of stroke, GDF11 is linked to regeneration and recovery through neovascularization, neurogenesis, and anti-inflammatory effects, among other potential mechanisms. Methods: Focal cerebral infarcts were made by permanent occlusion of the proximal right middle cerebral artery (MCA) by microbipolar coagulation, following a modification of the method of Tamura et al. rGDF11 or vehicle was delivered via multiple routes of administration to male Sprague Dawley Rats at single and multiple doses ranging from 0.1 - 4 mg/kg per dose. Dosing started ~24 hours following injury. Behavioral assessments (e.g., limb placement and body swing) were captured at days 3, 5, 7, 14, 21, and 28 post-injury. Results: Dose-dependent improvements in all behavioral assessments were seen at all animals receiving any dose level or frequency of rGDF11. Vehicle vs. rGDF11 comparisons yielded statistically significant improvements (p < 0.05) in all 3 behavioral assessments at several post-injury timepoints, including follow-up days 14 & 28. No major tolerability events were observed, and no animals were lost during the study. Histologic and serum markers indicated rGDF11’s beneficial effects on neovascularization, neurogenesis, and inflammation. Conclusions: Treatment of pMCAO rats with rGDF11 ~24hrs post-injury resulted in dose-dependent, durable improvements in motor function-focused behavioral assessments. These data support continued development of the potential clinical therapeutic application of rGDF11 in stroke and related disorders.

Delayed upregulation of the neuronal chloride extruder KCC2 underlies the progressive shift in GABA signaling polarity during development. Conversely, KCC2 downregulation is observed in a variety of neurological and psychiatric disorders often associated with cognitive impairment. Reduced KCC2 expression and function in mature networks may disrupt GABA signaling and promote anomalous network activities underlying these disorders. However, the causal link between KCC2 downregulation, altered brain rhythmogenesis and cognitive function remains elusive. Here, by combining behavioral exploration with in vivo electrophysiology we assessed the impact of chronic KCC2 silencing in mouse dorsal hippocampus and showed it compromises both spatial and contextual memory. This was associated with altered hippocampal rhythmogenesis and neuronal hyperexcitability, with increased CA1 pyramidal cell burst firing during non-REM sleep. Reducing neuronal excitability with terbinafine, a specific Task-3 leak potassium channel activator, occluded the impairment of contextual memory upon KCC2 silencing. Our results establish a causal relationship between KCC2 expression and cognitive performance and suggest that impaired rhythmopathies and neuronal hyperexcitability are central to the deficits caused by KCC2 silencing in the adult mouse brain.

Polarized hyphal growth of filamentous pathogenic fungi is an essential event for host penetration and colonization. The long-range early endosomal trafficking during hyphal growth is crucial for nutrient uptake, sensing of host-specific cues, and regulation of effector production. Bin1/Amphiphysin/Rvs167 (BAR) domain-containing proteins mediate fundamental cellular processes, including membrane remodeling and endocytosis. Here, we identified a F-BAR domain protein (ArF-BAR) in the necrotrophic fungus Ascochyta rabiei and demonstrate its involvement in endosome-dependent fungal virulence on the host plant Cicer arietinum. We show that ArF-BAR regulates endocytosis at the hyphal tip, localizes to the early endosomes, and is involved in actin dynamics. Functional studies involving gene knockout and complementation experiments reveal that ArF-BAR is necessary for virulence. The loss-of-function of ArF-BAR gene results in delayed formation of apical septum in fungal cells near growing hyphal tip that is crucial for host penetration, and impaired secretion of a candidate effector having secretory signal peptide for translocation across the endoplasmic reticulum membrane. The mRNA transcripts of ArF-BAR were induced in response to oxidative stress and infection. We also show that ArF-BAR is able to tubulate synthetic liposomes, suggesting the functional role of F-BAR domain in membrane tubule formation in vivo. Further, our studies identified a stress-induced transcription factor, ArCRZ1 (Calcineurin-responsive zinc finger 1), as key transcriptional regulator of ArF-BAR expression. We propose a model in which ArCRZ1 functions upstream of ArF-BAR to regulate A. rabiei virulence through a mechanism that involves endocytosis, effector secretion, and actin cytoskeleton regulation., Author summary BAR-domain superfamily is known to mold amorphous lipid bilayer into defined tubular shapes and required for endosome formation and trafficking. Although these proteins were studied earlier in context of their structural and biochemical properties, there is limited evidence on the direct role of F-BAR domain proteins in the pathophysiological development of other economically important fungi. Our study assumes functional significance for plant infection as we identified an F-BAR domain-containing protein that is regulated by a distinct transcriptional network regulated by a calcium-regulated CRZ1 transcription factor. We characterized ArF-BAR in a necrotrophic fungal pathogen, Ascochyta rabiei, which causes the Ascochyta blight disease of chickpea. Our study will help to understand a signaling cascade that regulates the formation of endosomes, which is required for fungal virulence.