Presynaptic residual calcium and synaptic facilitation at hippocampal synapses of mice with altered expression of SNAP-25

Abstract

Paired pulse facilitation (PPF) is a form of short-term synaptic plasticity that results from an interaction of residual presynaptic Ca2+ ([Ca2+]res), number of release-competent vesicles, and the sensitivity of the vesicle release mechanisms to Ca2+. While PPF is predominant at hippocampal Schaffer collateral-CA1 (SC-CA1) synapses, facilitation is greater in adult mice (designated Tkneo) that over express an isoform of the plasma membrane-targeted SNARE protein, SNAP-25a, which is normally predominantly expressed in juvenile animals. SNAP-25 is essential for action potential-dependent neuroexocytosis, yet the significance of the shift between the alternatively spliced variants SNAP-25a and SNAP-25b is not fully understood. This alteration of a key component of the protein machinery required for neurotransmitter release in Tkneo mice, therefore, provides a useful tool to further investigate presynaptic mechanisms that influence short-term plasticity. To explore this link between SNAP-25 and PPF, we simultaneously measured postsynaptic potentials and presynaptic [Ca2+]res during paired-pulses in adult Tkneo, heterozygote null (HET), and wild type (WT) mice. We demonstrate that enhanced PPF is maintained at mature hippocampal synapses of Tkneo mice that predominantly express SNAP-25a, and that [Ca2+]res kinetics are altered at synapses of Tkneo and HET mice, both of which exhibit reduced levels of total SNAP-25 expression. To evaluate the role of SNAP-25 in short-term plasticity and [Ca2+]res regulation, we applied a vesicular release probability model for neurotransmission. Our results suggest that the isoform expression and total level of SNAP-25 affect both [Ca2+]res dynamics and the ability of releasable vesicles to enter into a facilitated state.

Behavioral Phenotyping of Parkin-Deficient Mice: Looking for Early Preclinical Features of Parkinson's Disease

“…We did not observed differences in the input-output curve indicating a preservation of synaptic density in parkin −/− mice. Furthermore, short-term plasticity using a PPF protocol, which is mostly dependent on pre-synaptic calcium handling [62] , was unaltered in parkin −/− mice, suggesting a preserved pre-synaptic function in parkin −/− mice; however, Θ-burst stimulation triggered a long-term potentiation with lower amplitude in slices from parkin −/− mice compared to wild-type mice. Since synaptic plasticity is considered a neurophysiological basis of memory processing [63] , this observed decrease of Θ-burst-induced LTP amplitude in hippocampal slices from parkin −/− mice, further corroborates our behavioral results showing deficits of hippocampal-dependent memory performance in parkin −/− mice.…”

“…However, striatal synaptosomes from parkin −/− mice displayed a higher basal release of dopamine, but not of glutamate, thus ruling out energy shortage of compromised viability as a possible cause for this difference. The basal release also exhibited significant Ca 2+ -dependency – the so-called spontaneous vesicular release fraction –, although the majority of basal release is Ca 2+ -independent, and hence, transporter-dependent, thus of cytosolic origin [62] . Thus, the most parcimonous interpretation is that the parkin −/− mice have increased cytoplasmic dopamine level as a result of decreased vesicular monoamine transporter activity or a greater cytoplasmic dopamine outflow due to increased dopamine transporter density.…”

Parallel fiber to Purkinje cell synaptic impairment in a mouse model of spinocerebellar ataxia type 27

“…At a 50 ms interval, PPF was 232 ± 14% ( n = 14) in wild type and 293 ± 18% ( n = 18) in Fgf14 −/− mice ( p < 0.05, Mann-Whitney test); at 100 ms PPF was 170 ± 7% ( n = 14) in wild type and 217 ± 9% ( n = 18) in Fgf14 −/− mice ( p < 0.001, Mann-Whitney test); and a 150 ms PPF was 148 ± 4% ( n = 14) in wild type and 168 ± 7% ( n = 18) in Fgf14 −/− mice ( p < 0.05, Mann-Whitney test). Given that PPF is an accepted measure of presynaptic function attributed to residual Ca 2+ content in the presynaptic terminal (Wu and Saggau, 1994 ; Debanne et al, 1996 ; Scullin et al, 2012 ; Bornschein et al, 2013 ), these results suggest that PF to Purkinje neuron Fgf14 −/− connections exhibit impaired basal synaptic transmission associated with disrupted presynaptic function.…”

“…The combined increase in PPF, a form of short-term plasticity attributed to changes in residual pre-synaptic Ca 2+ (Wu and Saggau, 1994 ; Debanne et al, 1996 ; Scullin et al, 2012 ; Bornschein et al, 2013 ), and decrease in VGLUT1 expression levels raise the question of whether these two phenotypes are functionally correlated. Recent in vitro studies conducted in cultured granule neurons report a role of FGF14 in regulating presynaptic voltage-gated Ca 2+ (Cav) channels with implications for synaptic transmission (Yan et al, 2013 ).…”

Regulation of Ca2+channels by SNAP-25 via recruitment of syntaxin-1 from plasma membrane clusters

“…, 2013), and the reported effects were not seen in some studies (Tafoya et al. , 2006, 2008; Scullin et al. , 2012).…”