Local Presynaptic Activity Gates Homeostatic Changes in Presynaptic Function Driven by Dendritic BDNF Synthesis

Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
Neuron (Impact Factor: 15.05). 12/2010; 68(6):1143-58. DOI: 10.1016/j.neuron.2010.11.034
Source: PubMed


Homeostatic synaptic plasticity is important for maintaining stability of neuronal function, but heterogeneous expression mechanisms suggest that distinct facets of neuronal activity may shape the manner in which compensatory synaptic changes are implemented. Here, we demonstrate that local presynaptic activity gates a retrograde form of homeostatic plasticity induced by blockade of AMPA receptors (AMPARs) in cultured hippocampal neurons. We show that AMPAR blockade produces rapid (<3 hr) protein synthesis-dependent increases in both presynaptic and postsynaptic function and that the induction of presynaptic, but not postsynaptic, changes requires coincident local activity in presynaptic terminals. This "state-dependent" modulation of presynaptic function requires postsynaptic release of brain-derived neurotrophic factor (BDNF) as a retrograde messenger, which is locally synthesized in dendrites in response to AMPAR blockade. Taken together, our results reveal a local crosstalk between active presynaptic terminals and postsynaptic signaling that dictates the manner by which homeostatic plasticity is implemented at synapses.

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    • "For example, manipulations of spiking firing and/or depolarization in individual neurons can elicit scaling, even when the network as a whole is unchanged (Burrone et al., 2002; Ibata et al., 2008; Goold and Nicoll, 2010). However, there is evidence that presynaptic activity and network-level activity are also important (Rutherford et al., 1998; Stellwagen and Malenka, 2006; Jakawich et al., 2010). The network argument rests especially on the fact that two soluble, diffusible factors , brain-derived neurotrophic factor (BDNF) and the cytokine tumor necrosis factor alpha (TNFα), play important signaling roles for synaptic scaling. "

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    • "Also in a computational model, the general capacity of the brain to compensate for auditory deprivation was restricted to the maintenance of response characteristics of fibers with a high-SR and lowthreshold as otherwise the generation of a sufficient increase in discharge rate to compensate for deprived auditory input may be hampered (Schaette and Kempter, 2009, 2012). Consequently the overall compensating central network stability, which is able to modulate the strength of connected synapses following sensory deprivation (Turrigiano and Nelson, 2004; Goaillard and Marder, 2006; Rich and Wenner, 2007; Maffei and Turrigiano, 2008; Pozo and Goda, 2010), and which requires an increase in BDNF, as a key regulator of synaptic homeostasis and plasticity (Minichiello, 2009; Bramham et al., 2010; Jakawich et al., 2010), should be revised in the context of BDNF-dependent afferent-driven maturation steps in the periphery that occur with onset of sensory function. It is challenging to consider that changes in the surface expression of K V 3.1 in SGNs (see above) and presumptive subsequently altered spiking rates within the ascending pathway may be a prerequisite for central adaptation processes. "
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    ABSTRACT: Brain-derived neurotrophic factor, BDNF, is one of the most important neurotrophic factors acting in the peripheral and central nervous system. In the auditory system its function was initially defined by using constitutive knockout mouse mutants and shown to be essential for survival of neurons and afferent innervation of hair cells in the peripheral auditory system. Further examination of BDNF null mutants also revealed a more complex requirement during re-innervation processes involving the efferent system of the cochlea. Using adult mouse mutants defective in BDNF signaling, it could be shown that a tonotopical gradient of BDNF expression within cochlear neurons is required for maintenance of a specific spatial innervation pattern of outer hair cells and inner hair cells. Additionally, BDNF is required for maintenance of voltage-gated potassium channels (KV) in cochlear neurons, which may form part of a maturation step within the ascending auditory pathway with onset of hearing and might be essential for cortical acuity of sound-processing and experience-dependent plasticity. A presumptive harmful role of BDNF during acoustic trauma and consequences of a loss of cochlear BDNF during aging are discussed in the context of a partial reversion of this maturation step. We compare the potentially beneficial and harmful roles of BDNF for the mature auditory system with those BDNF functions known in other sensory circuits, such as the vestibular, visual, olfactory, or somatosensory system.
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    • "Similar to the Drosophila system, postsynaptic mammalian Target of Rapamycin Complex1 (mTORC1) drives this retrograde signaling process—albeit through release of Brain-Derived Neurotrophic Factor (BDNF), which is not found in Drosophila (Henry et al., 2012). Also resonant with the Drosophila NMJ, coincident application of a cocktail of N-and P/Q-type calcium channel blockers ω-conotoxin GVIA and ω-agatoxin IVA (CTx/ATx cocktail) completely abolishes the enhanced presynaptic activity induced by 3 h of CNQX exposure (Jakawich et al., 2010). This result supports the idea that presynaptic Ca V 2 function is required for this form of homeostatic plasticity. "
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    ABSTRACT: Throughout life, animals face a variety of challenges such as developmental growth, the presence of toxins, or changes in temperature. Neuronal circuits and synapses respond to challenges by executing an array of neuroplasticity paradigms. Some paradigms allow neurons to up- or downregulate activity outputs, while countervailing ones ensure that outputs remain within appropriate physiological ranges. A growing body of evidence suggests that homeostatic synaptic plasticity (HSP) is critical in the latter case. Voltage-gated calcium channels gate forms of HSP. Presynaptically, the aggregate data show that when synapse activity is weakened, homeostatic signaling systems can act to correct impairments, in part by increasing calcium influx through presynaptic CaV2-type channels. Increased calcium influx is often accompanied by parallel increases in the size of active zones and the size of the readily releasable pool of presynaptic vesicles. These changes coincide with homeostatic enhancements of neurotransmitter release. Postsynaptically, there is a great deal of evidence that reduced network activity and loss of calcium influx through CaV1-type calcium channels also results in adaptive homeostatic signaling. Some adaptations drive presynaptic enhancements of vesicle pool size and turnover rate via retrograde signaling, as well as de novo insertion of postsynaptic neurotransmitter receptors. Enhanced calcium influx through CaV1 after network activation or single cell stimulation can elicit the opposite response-homeostatic depression via removal of excitatory receptors. There exist intriguing links between HSP and calcium channelopathies-such as forms of epilepsy, migraine, ataxia, and myasthenia. The episodic nature of some of these disorders suggests alternating periods of stable and unstable function. Uncovering information about how calcium channels are regulated in the context of HSP could be relevant toward understanding these and other disorders.
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