Extracellular proton concentrations in the brain may be an important signal for neuron function. Proton concentrations change both acutely when synaptic vesicles release their acidic contents into the synaptic cleft and chronically during ischemia and seizures. However, the brain receptors that detect protons and their physiologic importance remain uncertain. Using organotypic hippocampal slices and biolistic transfection, we found the acid-sensing ion channel 1a (ASIC1a), localized in dendritic spines where it functioned as a proton receptor. ASIC1a also affected the density of spines, the postsynaptic site of most excitatory synapses. Decreasing ASIC1a reduced the number of spines, whereas overexpressing ASIC1a had the opposite effect. Ca 2؉ -mediated Ca 2؉ ͞calmodulin-dependent protein kinase II (CaMKII) signaling was probably responsible, because acid evoked an ASIC1a-dependent elevation of spine intracellular Ca 2؉ concentration, and reducing or increasing ASIC1a levels caused parallel changes in CaMKII phosphorylation in vivo. Moreover, inhibiting CaMKII prevented ASIC1a from increasing spine density. These data indicate that ASIC1a functions as a postsynaptic proton receptor that influences intracellular Ca 2؉ concentration and CaMKII phosphorylation and thereby the density of dendritic spines. The results provide insight into how protons influence brain function and how they may contribute to pathophysiology.Ca 2ϩ ͞calmodulin-dependent protein kinase II ͉ neuron ͉ sodium channel ͉ synapse W hen synaptic vesicles fuse with the presynaptic membrane, they release neurotransmitter into the synaptic cleft and activate neurotransmitter receptors on the postsynaptic membrane. Several measurements place synaptic vesicle pH at Ϸ5.2-5.7 (1-3). As a result, when synaptic vesicles discharge their contents, the pH at synapses may fall, especially during repeated discharge with release of multiple vesicles. Accordingly, several studies have detected acidification during synaptic transmission (4-6); for example, pH in the retinal ribbon synapse is estimated to drop 0.2-0.6 pH units during synaptic transmission (4, 6). In addition to physiological acidification during neurotransmission, central pH falls in disease states such as ischemia and seizure (7). Thus, understanding how protons regulate channels and its consequence on synapses may help us better understand neuronal function and provide insight into neurological diseases where acidosis is involved.Interesting candidates for sensing protons are acid-sensing ion channels (ASICs). ASICs are activated by extracellular protons. They belong to the degenerin͞epithelial Na ϩ channel family of nonvoltage gated cation channels (8-10). Four ASIC genes (ASIC1 to ASIC4) and splice variants (a and b) for ASIC1 and ASIC2 have been identified. ASIC subunits have two transmembrane domains and a large extracellular loop, and they function as homomultimers or heteromultimers to conduct Na ϩ and Ca 2ϩ . In the peripheral nervous system, ASICs contribute to mechanosensation, nocicept...

Spiral ganglion neurons (SGNs) require both pre-and postsynaptic contacts to maintain viability. BDNF, chlorphenylthiocAMP, and depolarization (veratridine

The mitochondrial signaling complex PKA/AKAP1 protects neurons against mitochondrial fragmentation and cell death by phosphorylating and inactivating the mitochondrial fission enzyme Drp1.

The dynamics of postsynaptic density (PSD) formation and remodeling were investigated in live developing hippocampal tissue slices. Time lapse imaging of transfected neurons expressing GFP-tagged PSD95, a prominent PSD protein, revealed that up to 40% of PSDs in developing dendrites are structurally dynamic; they rapidly (<15 min) appear or disappear, but also grow, shrink and move within shafts and spines. New spines containing PSDs were formed by conversion of dynamic filopodia-like spine precursors in which PSDs appeared de novo, or by direct extension of spines or spine precursors carrying preformed PSDs from the shaft. PSDs are therefore highly dynamic structures that can undergo rapid structural alteration within dendrite shafts, spines and spine precursors, permitting rapid formation and remodeling of synaptic connections in developing CNS tissues.

Spiral ganglion neurons (SGNs) are postsynaptic to hair cells and project to the brainstem. The inner hair cell (IHC) to SGN synapse is susceptible to glutamate excitotoxicity and to acoustic trauma, with potentially adverse consequences to long-term SGN survival. We used a cochlear explant culture from P6 rat pups consisting of a portion of organ of Corti maintained intact with the corresponding portion of spiral ganglion to investigate excitotoxic damage to IHC-SGN synapses in vitro. The normal innervation pattern is preserved in vitro. Brief treatment with NMDA and kainate results in loss of IHC–SGN synapses and degeneration of the distal type 1 SGN peripheral axons, mimicking damage to SGN peripheral axons caused by excitotoxicity or noise in vivo. The number of IHC presynaptic ribbons is not significantly altered. Reinnervation of IHCs occurs and regenerating axons remain restricted to the IHC row. However, the number of postsynaptic densities (PSDs) does not fully recover and not all axons regrow to the IHCs. Addition of either NT-3 or BDNF increases axon growth and synaptogenesis. Selective blockade of endogenous NT-3 signaling with TrkC-IgG reduced regeneration of axons and PSDs, but TrkB-IgG, which blocks BDNF, has no such effect, indicating that endogenous NT-3 is necessary for SGN axon growth and synaptogenesis. Remarkably, TrkC-IgG reduced axon growth and synaptogenesis even in the presence of BDNF, indicating that endogenous NT-3 has a distinctive role, not mimicked by BDNF, in promoting SGN axon growth in the organ of Corti and synaptogenesis on IHCs.