Patterned, Stimulus-Independent Neuronal Activity In the Developing Drosophila Visual System: Origin and Contribution to Synaptic Maturation

Project Summary/Abstract
Synaptic connections determine how neural circuits process information. Understanding how the strength and
specificity of these connections is established is a central challenge in neurobiology. In many parts of the
developing mammalian brain, stereotyped patterns of stimulus-independent neuronal activity precede sensory-
driven responses. Whether and how this developmental activity guides synapse assembly at the level of
defined cell types and circuits is not well-understood. Here, much of the challenge is due to the size and
complexity of the mammalian brain itself: Even in the retina, where developmental activity is best
characterized, the technical barriers to pursuing synapse level questions are significant. We recently
discovered analogous patterned, stimulus-independent neural activity (PSINA, pronounced `see-nah') in the
developing Drosophila brain. With the ever-growing knowledge of its neurobiology, spanning the connectome
to behavior, the fly is unmatched in its promise for cell type- and circuit- level studies. PSINA is globally
coordinated with brain-wide, periodic active and silent phases. In the visual system, each cell type participates
in PSINA with distinct and stereotyped spatio-temporal patterns of activity. These developmental activity
patterns are correlated between pairs of neurons known to be synaptic partners in the adult. Our long term
goal is to test the hypothesis that the cell-type-specific activity patterns of PSINA refine the emerging
connectome to generate wild-type synaptic strength and specificity. Here, we will work toward this goal by
leveraging a new genetic handle on PSINA: Trpγ, a cation channel with a weak preference for Ca2+, is required
for wild-type PSINA. In trpγ mutants, the amplitude of activity is reduced by >50% across the whole brain, and
cell-type-specific activity patterns and synapse numbers are altered. Trpγ is expressed in <1.5% of the
neurons in the brain. Notably, silencing only these neurons by overexpressing a hyperpolarizing channel
attenuates PSINA by >90%. This indicates that some or all of this diverse group of ~1,700 Trpγ-expressing (i.e.
Trpγ+) neurons are critical to coordinating PSINA in the developing brain. We hypothesize that Trpγ+ neurons
are the source of the cell-type-specific activity patterns. In Aim 1, we will identify individual Trpγ+ neurons that
innervate the visual system and test if these neurons specify the activity patterns of their post-synaptic
partners. Determining the origin of these patterns will allow us to ask whether they are the cause or
consequence of synapse and circuit maturation. In Aim 2, we will focus on a specific neuron that is part of the
well-studied motion detection circuit and ask if the strength of its post-synaptic contacts are altered in trpγ
mutants. Identifying the cellular origin of the activity patterns and understanding the effect of PSINA on
synaptic development will allow us to reversibly silence, alter, or possibly re-program PSINA. With this
knowledge, we will be able to define the contribution of developmental activity to the structural and functional
maturation of synapses and circuits, to sensory processing, to learning, memory, and behavior.

Grant Number: 5R01NS123376-05
NIH Institute/Center: NIH
Principal Investigator: Orkun Akin