Aberrant signaling through the Raf/MEK/ERK (ERK/MAPK) pathway causes pathology in a family of neurodevelopmental disorders known as 'RASopathies' and is implicated in autism pathogenesis. Here, we have determined the functions of ERK/MAPK signaling in developing neocortical excitatory neurons. Our data reveal a critical requirement for ERK/MAPK signaling in the morphological development and survival of large Ctip2+ neurons in layer 5. Loss of Map2k1/2 (Mek1/2) led to deficits in corticospinal tract formation and subsequent corticospinal neuron apoptosis. ERK/MAPK hyperactivation also led to reduced corticospinal axon elongation, but was associated with enhanced arborization. ERK/MAPK signaling was dispensable for axonal outgrowth of layer 2/3 callosal neurons. However, Map2k1/2 deletion led to reduced expression of Arc and enhanced intrinsic excitability in both layers 2/3 and 5, in addition to imbalanced synaptic excitation and inhibition. These data demonstrate selective requirements for ERK/MAPK signaling in layer 5 circuit development and general effects on cortical pyramidal neuron excitability.DOI: http://dx.doi.org/10.7554/eLife.11123.001

Paediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Traditionally, ongoing neurodevelopment and neuroplasticity have been considered to confer children with an advantage following TBI. However, recent findings indicate that the paediatric brain may be more sensitive to brain injury. Inhibitory interneurons are essential for proper cortical function and are implicated in the pathophysiology of TBI, yet few studies have directly investigated TBI-induced changes to interneurons themselves. Accordingly, in the present study, we examine how inhibitory neurons are altered following controlled cortical impact (CCI) in juvenile mice with targeted Cre-dependent fluorescence labelling of interneurons (Vgat:Cre/Ai9 and PV:Cre/Ai6). Although CCI failed to alter the number of excitatory neurons or somatostatin-expressing interneurons in the peri-injury zone, it significantly decreased the density of parvalbumin (PV) immunoreactive cells by 71%. However, PV:Cre/Ai6 mice subjected to CCI showed a lower extent of fluorescence labelled cell loss. PV interneurons are predominantly of a fast-spiking (FS) phenotype and, when recorded electrophysiologically from the peri-injury zone, exhibited intrinsic properties similar to those of control neurons. Synaptically, CCI induced a decrease in inhibitory drive onto FS interneurons combined with an increase in the strength of excitatory events. The results of the present study indicate that CCI induced both a loss of PV interneurons and an even greater loss of PV expression. This suggests caution is required when interpreting changes in PV immunoreactivity alone as direct evidence of interneuronal loss. Furthermore, in contrast to reports in adults, TBI in the paediatric brain selectively alters PV-FS interneurons, primarily resulting in a loss of interneuronal inhibition.

Despite divergent evolutionary origins, the organization of olfactory systems is remarkably similar across phyla. In both insects and mammals, sensory input from receptor cells is initially processed in synaptically dense regions of neuropil called glomeruli, where neural activity is shaped by local inhibition and centrifugal neuromodulation prior to being sent to higher order brain areas by projection neurons. Here we review both similarities and several key differences in the neuroanatomy of the olfactory system in honey bees, mice and humans, using a combination of literature review and new primary data. We have focused on the chemical identity and the innervation patterns of neuromodulatory inputs in the primary olfactory system. Our findings show that serotonergic fibers are similarly distributed across glomeruli in all three species. Octopaminergic/tyraminergic fibers in the honey bee also have a similar distribution, and possibly a similar function, to noradrenergic fibers in the mammalian OBs. However, preliminary evidence suggests that human OB may be relatively less organized than its counterparts in honey bee and mouse.

Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes.

The RAS/RAF/MEK/ERK1/2 intracellular signaling pathway is activated by numerous cues during brain development and dysregulated in neurodevelopmental syndromes, particularly the RASopathies and certain forms of autism. Cortical excitatory/inhibitory imbalance is thought to be critical in the neuropathogenesis of these conditions. However, the developmental functions of ERK1/2 signaling in cortical inhibitory neurons (CINs) and other medial ganglionic eminence (MGE)-derived non-neuronal cells are poorly understood. Here, we genetically modulated ERK1/2 signaling in mouse MGE neural progenitors or GABAergic neurons in vivo. We find that MEK-ERK1/2 signaling is essential for regulating MGE-derived oligodendrocyte number in the anterior commissure. While Erk1/2 inactivation does not alter CIN number, we show that CIN-autonomous ERK1/2 signaling is necessary for chemogenetic activity-dependent FOSB expression in vivo. This deficit coincides with a significant and persistent reduction in somatostatin, but not parvalbumin, expression in a subset of ERK1/2 deleted inhibitory neurons. Interestingly, one week of chronic chemogenetic stimulation in juvenile or adult animals partially rescues the decrease in somatostatin expression in Erk1/2 mutant CINs. Our data demonstrate ERK1/2 signaling is required for the establishment of MGE-derived glia, whereas in CINs, ERK1/2 drives activity dependent-responses and the expression of somatostatin in a subset of neurons.