ABSTRACT
Dendritic spines compartmentalize information in the brain, and their morphological characteristics are thought to underly synaptic plasticity. Here we identify copine-6 as a novel modulator of dendritic spine morphology. We found that brain-derived neurotrophic factor (BDNF) - a molecule essential for long-term potentiation of synaptic strength - upregulated and recruited copine-6 to dendritic spines in hippocampal neurons. Overexpression of copine-6 increased mushroom spine number and decreased filopodia number, while copine-6 knockdown had the opposite effect and dramatically increased the number of filopodia, which lacked PSD95. Functionally, manipulation of post-synaptic copine-6 levels affected miniature excitatory post-synaptic current (mEPSC) kinetics and evoked synaptic vesicle recycling in contacting boutons, and post-synaptic knockdown of copine-6 reduced hippocampal LTP and increased LTD. Mechanistically, copine-6 promotes BDNF-TrkB signaling and recycling of activated TrkB receptors back to the plasma membrane surface, and is necessary for BDNF-induced increases in mushroom spines in hippocampal neurons. Thus copine-6 regulates BDNF-dependent changes in dendritic spine morphology to promote synaptic plasticity.
Subject(s)
Carrier Proteins/metabolism , Dendritic Spines/physiology , Hippocampus/cytology , Nerve Tissue Proteins/metabolism , Neurons/physiology , Neurons/ultrastructure , Synaptic Vesicles/physiology , Animals , Brain-Derived Neurotrophic Factor/pharmacology , Carrier Proteins/genetics , Cells, Cultured , Dendritic Spines/ultrastructure , Disks Large Homolog 4 Protein/metabolism , Humans , Mice , Microtubule-Associated Proteins/metabolism , Nerve Tissue Proteins/genetics , Organ Culture Techniques , Rats , Receptor, trkB/genetics , Receptor, trkB/metabolism , Synapses/drug effects , Synapses/physiology , Synapses/ultrastructure , Synaptic Potentials/drug effects , Synaptic Potentials/genetics , Synaptic Vesicles/drug effects , Synaptosomes/metabolism , Synaptosomes/ultrastructure , Vesicular Glutamate Transport Protein 1/metabolism , Vesicular Inhibitory Amino Acid Transport Proteins/metabolismABSTRACT
TRPV1 is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons. However, the location and function of TRPV1 in the hippocampus is debated. We found that TRPV1 is expressed in oriens-lacunosum-moleculare (OLM) interneurons in the hippocampus, and promotes excitatory innervation. TRPV1 knockout mice have reduced glutamatergic innervation of OLM neurons. When activated by capsaicin, TRPV1 recruits more glutamatergic, but not GABAergic, terminals to OLM neurons in vitro. When TRPV1 is blocked, glutamatergic input to OLM neurons is dramatically reduced. Heterologous expression of TRPV1 also increases excitatory innervation. Moreover, TRPV1 knockouts have reduced Schaffer collateral LTP, which is rescued by activating OLM neurons with nicotine-via α2ß2-containing nicotinic receptors-to bypass innervation defects. Our results reveal a synaptogenic function of TRPV1 in a specific interneuron population in the hippocampus, where it is important for gating hippocampal plasticity.
Subject(s)
Hippocampus/cytology , Interneurons/physiology , TRPV Cation Channels/metabolism , Animals , Brain-Derived Neurotrophic Factor/metabolism , Calcium/metabolism , Capsaicin/pharmacology , Female , Hippocampus/drug effects , Long-Term Potentiation/physiology , Male , Mice, Knockout , Neuronal Plasticity , Nicotine/pharmacology , Patch-Clamp Techniques , Rats, Wistar , Receptors, Nicotinic/metabolism , TRPV Cation Channels/geneticsABSTRACT
Crustaceans have frequently been used to study the neuroethology of both agonistic behavior and circadian rhythms, but whether their highly stereotyped and quantifiable agonistic activity is controlled by circadian pacemakers has, so far, not been investigated. Isolated marbled crayfish (Procambarus spec.) displayed rhythmic locomotor activity under 12-h light:12-h darkness (LD12:12) and rhythmicity persisted after switching to constant darkness (DD) for 8 days, suggesting the presence of endogenous circadian pacemakers. Isogenetic females of parthenogenetic marbled crayfish displayed all behavioral elements known from agonistic interactions of previously studied decapod species including the formation of hierarchies. Groups of marbled crafish displayed high frequencies of agonistic encounters during the 1st hour of their cohabitation, but with the formation of hierarchies agonistic activities were subsequently reduced to low levels. Group agonistic activity was entrained to periods of exactly 24 h under LD12:12, and peaks of agonistic activity coincided with light-to-dark and dark-to-light transitions. After switching to DD, enhanced agonistic activity was dispersed over periods of 8-to 10-h duration that were centered around the times corresponding with light-to-dark transitions during the preceding 3 days in LD12:12. During 4 days under DD agonistic activity remained rhythmic with an average circadian period of 24.83 +/- 1.22 h in all crayfish groups tested. Only the most dominant crayfish that participated in more than half of all agonistic encounters within the group revealed clear endogenous rhythmicity in their agonistic behavior, whereas subordinate individuals, depending on their social rank, initiated only between 19.4% and 0.03% of all encounters in constant darkness and displayed no statistically significant rhythmicity. The results indicate that both locomotion and agonistic social interactions are rhythmic behaviors of marbled crayfish that are controlled by light-entrained endogenous pacemakers.
