Role of Efficient Neurotransmitter Release in Barrel Map Development

Abstract

Cortical maps are remarkably precise, with organized arrays of thalamocortical afferents (TCAs) that project into distinct neuronal modules. Here, we present evidence for the involvement of efficient neurotransmitter release in mouse cortical barrel map development using barrelless mice, a loss-of-function mutant of calcium/calmodulin-activated adenylyl cyclase I (AC1), and mice with a mutation in Rab3-interacting molecule 1␣ (RIM1␣), an active zone protein that regulates neurotransmitter release. We demonstrate that release efficacy is substantially decreased in barrelless TCAs. We identify RIMs as important phosphorylation targets for AC1 in the presynaptic terminal. We further show that RIM1␣ mutant mice have reduced TCA neurotransmitter release efficacy and barrel map deficits, although not as severe as those found in barrelless mice. This supports the role of RIM proteins in mediating, in part, AC1 signaling in barrel map development. Finally, we present a model to show how inadequacies in presynaptic function can interfere with activitydependent processes in neuronal circuit formation. These results demonstrate how efficient synaptic transmission mediated by AC1 function contributes to the development of cortical barrel maps.

Distinct regional and subcellular localization of adenylyl cyclases type 1 and 8 in mouse brain

“…This hypothesis is based on the significant reduction of mossy fiber LTP in AC1KO mice (Villacres et al, 1998). Recent evidence from barrelless mice also suggests a presynaptic role for AC1 in neurotransmission (Lu et al, 2006). Specifically, AC1 deficiency in these mice results in impaired phosphorylation of Rab3-interacting molecules, which are active zone proteins essential to neurotransmission.…”

“…High expression of AC1 in the parallel fiberPurkinje cell synapse in the cerebellum suggests a presynaptic role for AC1 , while disruption of LTP and long-term depression (LTD) at the thalamocortical synapse in AC1 "barrelless" mutant mice is demonstrated to be an AC1-dependent postsynaptic phenomenon (Lu et al, 2003). Recent evidence from barrelless mice has likewise implicated AC1 in the presynaptic regulation of neurotransmission (Lu et al, 2006). Although limited, data regarding the subcellular distribution of AC8 reveals its co-localization with both presynaptic and postsynaptic proteins upon transfection into cortical and hippocampal neurons in vitro (Wang et al, 2003).…”

Developmental Homeostasis of Mouse Retinocollicular Synapses

“…Stable whole-cell voltageclamp recordings were established at Ϫ70 mV holding potential, and extracellular Ca 2ϩ in the bath ACSF was replaced with 3 mM Sr 2ϩ . Sr 2ϩ desynchronizes vesicle release, allowing evoked miniature currents events to be analyzed (Goda and Stevens, 1994;Xu-Friedman and Regehr, 1999;Lu et al, 2006). Evoked miniature events were recorded in 1 s epochs every 5-10 s in IgorPro, and subsequently imported into Mini Analysis software (Synaptosoft, Decatur, GA).…”

Neurofibromin Is Required for Barrel Formation in the Mouse Somatosensory Cortex

“…This is best exemplified by transplantation studies demonstrating formation of barrels in visual cortex explants when they are placed in the somatosensory cortex and innervated by VPM thalamic axons (Schlaggar and O'Leary, 1991). Several lines of mouse genetic mutants have been generated that exhibit defects in the development of cortical barrels despite partial Hannan et al, 2001) or normal (Iwasato et al, 2000;Inan et al, 2006;Lu et al, 2006;Watson et al, 2006) thalamic axonal segregation. The phenotypes of the NF1 conditional knock-outs are similar to these mutants, further confirming the notion that signaling activities in the postsynaptic cortical neurons are critical in their rearrangement in response to thalamic cues.…”