Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca ²⁺ entry pathway

Abstract

At central synapses, P͞Q-type Ca 2؉ channels normally provide a critical Ca 2؉ entry pathway for neurotransmission. Nevertheless, we found that nerve terminals lacking ␣1A (CaV2.1), the pore-forming subunit of P͞Q-type channels, displayed a remarkable preservation of synaptic function. Two consistent physiological changes reflective of synaptic homeostasis were observed in cultured hippocampal neurons derived from ␣1A (؊/؊) mice. First, the presynaptic response to an ionophore-mediated Ca 2؉ elevation was 50% greater, indicating an enhanced Ca 2؉ sensitivity of the release machinery. Second, basal miniature excitatory postsynaptic current frequency in ␣1A (؊/؊) neurons was increased 2-fold compared with WT neurons and occluded the normal response of presynaptic terminals to cAMP elevation, suggesting that the compensatory mechanism in ␣1A (؊/؊) synapses and the modulation of presynaptic function by PKA might share a final common pathway. We used cDNA microarray analysis to identify molecular changes underlying homeostatic regulation in the ␣1A (؊/؊) hippocampus. The 40,000 entries in our custom-made array included likely targets of presynaptic homeostasis, along with many other transcripts, allowing a wide-ranging examination of gene expression. The developmental pattern of changes in transcript levels relative to WT was striking; mRNAs at 5 and 11 days postnatal showed little deviation, but clear differences emerged by 22 days. Many of the transcripts that differed significantly in abundance corresponded to known genes that could be incorporated within a logical pattern consistent with the modulation of presynaptic function. Changes in endocytotic proteins, signal transduction kinases, and candidates for Ca 2؉ -sensing molecules were consistent with implications of the direct physiological experiments.

Modulation of Presynaptic Plasticity and Learning by the H-ras/Extracellular Signal-Regulated Kinase/Synapsin I Signaling Pathway

“…The demonstration of enhanced neurotransmitter release during high-frequency stimulation is further supported by the associated increase in docked neurotransmitter vesicles at presynaptic active zones of H-ras G12V mice and an increased frequency but not amplitude of mEPSCs. Interestingly, although PPF, STP, mEPSC frequency, and the density of docked vesicles were all increased, baseline synaptic transmission was maintained, likely mediated through presynaptic homeostatic plasticity (Davis and Goodman, 1998;Jones et al, 1998;Daniels et al, 2004;Piedras-Renteria et al, 2004). Together, these data suggest that the LTP enhancements in H-ras G12V mice do not result from changes in postsynaptic plasticity but rather from a frequencydependent facilitation of short-term presynaptic plasticity leading to increased neurotransmitter release specifically during high-frequency LTP induction.…”

Synaptic Vesicle Recycling Adapts to Chronic Changes in Activity

“…Second, calcium dynamics in presynaptic terminals and calcium sensitivity of neurotransmitter release is unlikely to have changed significantly, because such a modification would have been reflected in initial synaptic response amplitudes. Molecular changes, in contrast, may involve the numerous targets in the presynaptic terminals including synaptotagmin 7, which can be regulated by global changes in activity (Piedras-Renteria et al, 2004), and different splice variants can alter vesicle trafficking pathways without significant alteration in kinetics of exocytosis or synapse morphology (Virmani et al, 2003). Chronic changes in the abundance of other critical synaptic vesicle recycling proteins or the efficacy of signaling cascades such as phosphoinositide turnover may also contribute to the activity-dependent modifications in vesicle trafficking (Micheva et al, 2003;Murthy and De Camilli, 2003).…”

Developmental Activation of Calmodulin-Dependent Facilitation of Cerebellar P-Type Ca2+Current

“…Third, over an even longer timescale, CDF induced over multiple stimuli could activate gene transcription and remodeling (Bradley and Finkbeiner, 2002;Kirov et al, 2004;Konur and Ghosh, 2005), perhaps contributing to pruning of multiple climbing-fiber innervations on single Purkinje neurons (Miyazaki et al, 2004). Similarly, in the brain as a whole, the 2-3 week postnatal period features the onset of obvious pathology in ␣ 1 2.1 knock-out mice (Jun et al, 1999;Fletcher et al, 2001;Urbano et al, 2003;Miyazaki et al, 2004;Piedras-Renteria et al, 2004), contemporaneous with overall upregulation of EFa channels (Vigues et al, 2002;Chaudhuri et al, 2004). These considerations, with our experiments linking neuronal CDF and EFa channels, suggest that CaMmediated facilitation may be central to the neurobiological function of Ca V 2.1.…”

“…Ca V 2.1 Ca 2ϩ channels (P-type) trigger neurotransmitter release (Dunlap et al, 1995), support neuroarchitectural development (Miyazaki et al, 2004), and impact molecular expression profiles optimizing presynaptic function (Piedras-Renteria et al, 2004). Aberrant function of these channels also mediate diseases ranging from Lambert-Eaton syndrome (Flink and Atchison, 2003) to heritable ataxia, epilepsy, and migraine (Ophoff et al, 1996;Zhuchenko et al, 1997).…”