Neurons integrate and encode complex synaptic inputs into action potential outputs through a process termed "intrinsic excitability." Here, we report the essential contribution of fibroblast growth factor homologous factors (FHFs), a family of voltage-gated sodium channel binding proteins, to this process. Fhf1-/-Fhf4-/- mice suffer from severe ataxia and other neurological deficits. In mouse cerebellar slice recordings, WT granule neurons can be induced to fire action potentials repetitively (approximately 60 Hz), whereas Fhf1-/-Fhf4-/- neurons often fire only once and at an elevated voltage spike threshold. Sodium channels in Fhf1-/-Fhf4-/- granule neurons inactivate at more negative membrane potential, inactivate more rapidly, and are slower to recover from the inactivated state. Altered sodium channel physiology is sufficient to explain excitation deficits, as tested in a granule cell computer model. These findings offer a physiological mechanism underlying human spinocerebellar ataxia induced by Fhf4 mutation and suggest a broad role for FHFs in the control of excitability throughout the CNS.

Miconieae is the most diverse tribe of Melastomataceae, with 30 genera and over 2200 species. The tribe is characterized by fleshy fruits and partially to totally inferior ovaries. To test monophyly of the tribe and assess phylogenetic relationships within it, sequence data from nrITS were gathered and analyzed for 110 taxa in Miconieae and 32 putative outgroups. The tribe Miconieae is not resolved as monophyletic, but rather composed of two distinct clades: one composed of the cauliflorous genera Henriettea, Henriettella, Loreya and Bellucia, and a second clade with all other taxa in Miconieae, sister to a polytomy that includes representatives from tribes Merianieae and Blakeeae. Terminal inflorescences are optimized as basal within Miconieae, with lateral inflorescences evolving in at least four different instances. Cauliflory does not appear to be derived from truly axillary inflorescences; instead it seems to have evolved independently. The terminal–flowered genera Tococa, Conostegia, Tetrazygia, Anaectocalyx, Charianthus, Calycogonium, and Leandra pro parte seem to be derived from within the large genus Miconia, as is Clidemia, a genus with both axillary inflorescences and terminal inflorescences that are deflexed to a lateral position by an axillary branch. Maieta and Necranium, both with axillary inflorescences, are resolved as derived from within Clidemia.

Deletion of the human SHANK3 gene near the terminus of chromosome 22q is associated with Phelan-McDermid syndrome and autism spectrum disorders. Nearly all such deletions also span the tightly linked IB2 gene. We show here that IB2 protein is broadly expressed in the brain and is highly enriched within postsynaptic densities. Experimental disruption of the IB2 gene in mice reduces AMPA and enhances NMDA receptor-mediated glutamatergic transmission in cerebellum, changes the morphology of Purkinje cell dendritic arbors, and induces motor and cognitive deficits suggesting an autism phenotype. These findings support a role for human IB2 mutation as a contributing genetic factor in Chr22qter-associated cognitive disorders.

Summary Recent studies in humans and in genetic mouse models have identified Slitrks as candidate genes for neuropsychiatric disorders. All Slitrk isotypes are highly expressed in the CNS, where they mediate neurite outgrowth, synaptogenesis and neuronal survival. However, the molecular mechanisms underlying these functions are not known. Here, we report that Slitrk5 modulates BDNF-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a trans-synaptic binding partner, PTPδ; however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. In the absence of Slitrk5, TrkB has a reduced rate of ligand-dependent recycling and altered responsiveness to BDNF treatment. Structured illumination microscopy revealed that Slitrk5 mediates optimal targeting of TrkB receptors to Rab11-positive recycling endosomes through the recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling.

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Background Anandamide (AEA)-dependent signaling is regulated by the catabolic enzyme fatty acid amide hydrolase (FAAH). Several lines of evidence have demonstrated that FAAH and AEA are involved in the behavioral effects of alcohol. Therefore, we investigated whether a selective FAAH inhibitor, URB597 (Cyclohexylcarbamic acid 3′-[aminocarbonyl]-[1,1′-biphenyl]-3-yl ester), altered alcohol intake in mice in a voluntary alcohol drinking model. Methods Mice, subjected to 3 weeks of chronic intermittent access (IA) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We evaluated the pharmacological effects of URB597 after both acute (1-day) withdrawal from chronic IA and 1-week withdrawal using the alcohol deprivation effect (ADE) model. AEA and N-acyl ethanolamide (NAE) abundances were determined after chronic IA, acute (1-day) or long-term (1 and 2 weeks) withdrawal in four brain regions. Results Acute pretreatment with URB597 reduced alcohol intake and preference after acute withdrawal. This effect was blocked by pretreatment with a selective type 1 cannabinoid receptor (CB1) antagonist, suggesting a CB1-mediated mechanism. Both single- and multiple- dosing regimens with an effective dose of URB597 prevented the ADE, with no tolerance development after the multi-dosing regimen. AEA and NAE levels were transiently increased in all brain regions measured after acute withdrawal, indicating that the endocannabinoid system is involved in acute alcohol withdrawal stress response. Conclusion FAAH inhibitors reduce alcohol escalation and “relapse” drinking in mice.

A human variant in the BDNF gene (Val66Met; rs6265) is associated with impaired fear extinction. Using super-resolution imaging, we demonstrate that the BDNF Met prodomain disassembles dendritic spines and eliminates synapses in hippocampal neurons. In vivo, ventral CA1 (vCA1) hippocampal neurons undergo similar morphological changes dependent on their transient co-expression of a SorCS2/p75 receptor complex during peri-adolescence. BDNF Met prodomain infusion into the vCA1 during this developmental time frame reduces dendritic spine density and prelimbic (PL) projections, impairing cued fear extinction. Adolescent Bdnf mice display similar spine and PL innervation deficits. Using fiber photometry, we found that, in wild-type mice, vCA1 neurons projecting to the PL encode extinction by enhancing neural activity in threat anticipation and rapidly subsiding their response. This adaptation is absent in BDNF mice. We conclude that the BDNF Met prodomain renders vCA1-PL projection neurons underdeveloped, preventing their capacity for subsequent circuit modulation necessary for fear extinction. VIDEO ABSTRACT.