Disruption of Cholinergic Retinal Waves Alters Visual Cortex Development and Function.

Retinal waves represent an early form of patterned spontaneous neural activity in the visual system. These waves originate in the retina before eye-opening and propagate throughout the visual system, influencing the assembly and maturation of subcortical visual brain regions. However, because it is technically challenging to ablate retina-derived cortical waves without inducing compensatory activity, the role these waves play in the development of the visual cortex remains unclear. To address this question, we used targeted conditional genetics to disrupt cholinergic retinal waves and their propagation to select regions of primary visual cortex, which largely prevented compensatory patterned activity. We find that loss of cholinergic retinal waves without compensation impaired the molecular and synaptic maturation of excitatory neurons located in the input layers of visual cortex, as well as layer 1 interneurons. These perinatal molecular and synaptic deficits also relate to functional changes observed at later ages. We find that the loss of perinatal cholinergic retinal waves causes abnormal visual cortex retinotopy, mirroring changes in the retinotopic organization of gene expression, and additionally impairs the processing of visual information. We further show that retinal waves are necessary for higher order processing of sensory information by impacting the state-dependent activity of layer 1 interneurons, a neuronal type that shapes neocortical state-modulation, as well as for state-dependent gain modulation of visual responses of excitatory neurons. Together, these results demonstrate that a brief targeted perinatal disruption of patterned spontaneous activity alters early cortical gene expression as well as synaptic and physiological development, and compromises both fundamental and, notably, higher-order functions of visual cortex after eye-opening.

Layer 1 neocortex: Gating and integrating multidimensional signals.

Layer 1 (L1) of the neocortex acts as a nexus for the collection and processing of widespread information. By integrating ascending inputs with extensive top-down activity, this layer likely provides critical information regulating how the perception of sensory inputs is reconciled with expectation. This is accomplished by sorting, directing, and integrating the complex network of excitatory inputs that converge onto L1. These signals are combined with neuromodulatory afferents and gated by the wealth of inhibitory interneurons that either are embedded within L1 or send axons from other cortical layers. Together, these interactions dynamically calibrate information flow throughout the neocortex. This review will primarily focus on L1 within the primary sensory cortex and will use these insights to understand L1 in other cortical areas.

Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing.

Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons in mouse somatosensory cortex is activity dependent. We then investigated the relationship between activity, alternative splicing, and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation.

Microglia contribute to the postnatal development of cortical somatostatin-positive inhibitory cells and to whisker-evoked cortical activity.

Microglia play a key role in shaping the formation and refinement of the excitatory network of the brain. However, less is known about whether and how they organize the development of distinct inhibitory networks. We find that microglia are essential for the proper development of somatostatin-positive (SST+) cell synapses during the second postnatal week. We further identify a pair of molecules that act antagonistically to one another in the organization of SST+ cell axonal elaboration. Whereas CX3CL1 acts to suppress axonal growth and complexity, CXCL12 promotes it. Assessing the functional importance of microglia in the development of cortical activity, we find that a whisker stimulation paradigm that drives SST+ cell activation leads to reduced cortical spiking in brains depleted of microglia. Collectively, our data demonstrate an important role of microglia in regulating the development of SST+ cell output early in life.

Bottom-up inputs are required for establishment of top-down connectivity onto cortical layer 1 neurogliaform cells.

Higher-order projections to sensory cortical areas converge on layer 1 (L1), the primary site for integration of top-down information via the apical dendrites of pyramidal neurons and L1 GABAergic interneurons. Here we investigated the contribution of early thalamic inputs onto L1 interneurons for establishment of top-down connectivity in the primary visual cortex. We find that bottom-up thalamic inputs predominate during L1 development and preferentially target neurogliaform cells. We show that these projections are critical for the subsequent strengthening of top-down inputs from the anterior cingulate cortex onto L1 neurogliaform cells. Sensory deprivation or selective removal of thalamic afferents blocked this phenomenon. Although early activation of the anterior cingulate cortex resulted in premature strengthening of these top-down afferents, this was dependent on thalamic inputs. Our results demonstrate that proper establishment of top-down connectivity in the visual cortex depends critically on bottom-up inputs from the thalamus during postnatal development.