Developmental Increase of Neocortical Presynaptic Efficacy via Maturation of Vesicle Replenishment

Abstract

The efficacy of neocortical synapses to transmit during bursts of action potentials (APs) increases during development but the underlying mechanisms are largely unclear. We investigated synaptic efficacy at synapses between layer 5 pyramidal neurons (L5PNs) during development, using paired recordings, presynaptic two-photon Ca 2+ imaging, and numerical simulations. Our data confirm a developmental increase in paired-pulse ratios (PPRs). Independent of age, Ca 2+ imaging revealed no AP invasion failures and linear summation of presynaptic Ca 2+ transients, making differences in Ca 2+ signaling an unlikely reason for developmental changes in PPR. Cumulative excitatory postsynaptic current (EPSC) amplitudes indicate that neither the size of the readily-releasable pool (RRP) nor replenishment rates were different between age groups, while the time-courses of depression differed significantly. At young synapses, EPSCs depressed rapidly to near steady-state during the first four APs, and synaptic failures (F syn) increased from 0 to 30%. At mature synapses this drop was significantly slower and strongly biphasic, such that near steady-state depression was reached not before 18 APs with F syn remaining between 0 and 5%. While young synapses reliably transmitted during pairs of APs, albeit with strong depression, mature synapses maintained near 100% transfer efficacy with significantly less depression during high-frequency bursts of APs. Our analysis indicates that at mature synapses a replenishment pool (RepP) is responsible for their high efficacy during bursting activity, while this RepP is functionally immature at young synapses. Hence, our data provide evidence that the functional maturation of a RepP underlies increasing synaptic efficacy during the development of an excitatory cortical synapse.

Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder

“…Additionally, BTBR mice display IL-NAc paired-pulse facilitation at P15 and P30 compared to C57BL/6J mice, suggesting reduced presynaptic glutamate release from IL terminals onto MSNs in BTBR mice. The difference in PPR between C57BL/6J and BTBR mice at P15 and P30 was observed using long (250 ms) and short (100 ms) interstimulus intervals, respectively, which might be influenced by developmental differences in presynaptic short-term plasticity, as reported previously [102][103][104] In the Shank3B -/mouse model of ASD, an accelerated maturation of striatal spiny projecting neurons (SPNs) of the dorsomedial striatum (DMS) was observed during early developmental stages (third and fourth postnatal weeks), followed by a decrease in corticostriatal activity during adulthood (P60) 105,106 -a deficit that was attributed to an overactivation of cortical circuits. Moreover, the authors found that increasing anterior cingulate cortex (ACC) synaptic drive to SPNs of DMS at P8 significantly increased SPN mEPSC frequency, whereas increasing ACC activity from P15 and older reduced SPN mEPSC frequency 106 , suggesting a developmental switch in the effect of cortical hyperactivity on SPN synaptic transmission.…”

“…Additionally, BTBR mice display IL-NAc paired-pulse facilitation at P15 and P30 compared to C57BL/6J mice, suggesting reduced presynaptic glutamate release from IL terminals onto MSNs in BTBR mice. The difference in PPR between C57BL/6J and BTBR mice at P15 and P30 was observed using long (250 ms) and short (100 ms) interstimulus intervals, respectively, which might be influenced by developmental differences in presynaptic short-term plasticity, as reported previously 102–104…”

Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder

“…Additionally, BTBR mice display IL-NAc paired-pulse facilitation at P15 and P30 compared to C57BL/6J mice, suggesting reduced presynaptic glutamate release from IL terminals onto MSNs in BTBR mice. The difference in PPR between C57BL/6J and BTBR mice at P15 and P30 was observed using long (250 ms) and short (100 ms) interstimulus intervals, respectively, which might be in uenced by developmental differences in presynaptic short-term plasticity, as reported previously [102][103][104] In the Shank3B -/mouse model of ASD, an accelerated maturation of striatal spiny projecting neurons (SPNs) of the dorsomedial striatum (DMS) was observed during early developmental stages (third and fourth postnatal weeks), followed by a decrease in corticostriatal activity during adulthood (P60) 105,106a de cit that was attributed to an overactivation of cortical circuits. Moreover, the authors found that increasing anterior cingulate cortex (ACC) synaptic drive to SPNs of DMS at P8 signi cantly increased SPN mEPSC frequency, whereas increasing ACC activity from P15 and older reduced SPN mEPSC frequency 106 , suggesting a developmental switch in the effect of cortical hyperactivity on SPN synaptic transmission.…”

Quantal analysis estimates docking site occupancy determining short‐term depression at hippocampal glutamatergic synapses

“…2020; Bornschein et al . 2020). In the model without SV replenishment of the docking sites, the cumulative plot (filled squares) stayed along the parabola fitting the standard variance‐mean plot (open circles; Fig.…”