Biology subjects

Rees, K. P.

Publications and source records attributed to Rees, K. P..

3 recordsLinked to original sources

bioRxiv2023

Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning

Abnormal Extracellular Regulated Kinase 1/2 (ERK1/2) signaling is linked to multiple neurodevelopmental diseases, especially the RASopathies, which typically exhibit ERK1/2 hyperactivation in neurons and non-neuronal cells. To better understand how excitatory neuron-autonomous ERK1/2 activity regulates the development of the mouse motor cortex, we conditionally expressed a hyperactive MEK1S217/221E variant using Nex/NeuroD6:Cre. Our results show that MEK1S217/221E expression led to persistent hyperactivation of ERK1/2 in neocortical axons, but not excitatory neuron somas or nuclei. We noted reduced axonal arborization of multiple subcortical target domains in mutants and reduced cortical expression of the activity dependent gene, ARC. These changes did not coincide with significant differences in voluntary locomotor activity or motor performance in the accelerating rotarod task. However, motor learning in a single-pellet retrieval task was significantly diminished in Nex/NeuroD6:Cre; MEK1S217/221E mutants. Restriction of MEK1S217/221E expression to layer V cortical neurons recapitulated axonal outgrowth deficits, however, had no effect on motor learning. Collectively, these results indicate that within the cortex, glutamatergic neuron-autonomous hyperactivation of MEK1 is sufficient to drive deficits in axon outgrowth, activity dependent gene expression, and skilled motor learning. Summary statementMEK-ERK1/2 hyperactivation in developing cortical excitatory neurons is sufficient to decrease long-range axonal outgrowth, which coincides with reduced Arc expression and deficits in aspects of skilled motor learning by adulthood.

neuroscience↗

bioRxiv2022

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

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 discovered a significant and persistent reduction in somatostatin, but not parvalbumin, expression in a subset of CINs. ERK1/2 signaling is also necessary for chemogenetic activity-dependent FOSB expression in CINs in vivo. 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.

neuroscience↗

bioRxiv2019

Hyperactive MEK1 signaling in cortical GABAergic interneurons causes embryonic parvalbumin-neuron death and deficits in behavioral inhibition

Abnormal ERK/MAPK pathway activity is an important contributor to the neuropathogenesis of many disorders including Fragile X, Rett, 16p11.2 Syndromes, and the RASopathies. Individuals with these syndromes often present with intellectual disability, ADHD, autism, and epilepsy. However, the pathological mechanisms that underly these deficits are not fully understood. Here, we examined whether hyperactivation of MEK1 signaling 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 subpallium. Adult mutants displayed a significant loss of mature parvalbumin-expressing (PV) CINs, but not somatostatin-expressing CINs, during postnatal development and a modest reduction in perisomatic inhibitory synapse formation on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype and minor differences in intrinsic electrophysiological properties. These changes 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 in the developing brain. Indeed, we found that mutants exhibit a significant impairment in the acquisition of a behavioral test that relies on behavioral response inhibition, a process linked to ADHD-like phenotypes. Overall, our data suggests PV-CIN development is particularly sensitive to hyperactive MEK1 signaling which may underlie neurological deficits frequently observed in ERK/MAPK-linked syndromes.\n\nSignificance StatementThe RASopathies are a family of neurodevelopmental syndromes caused by mutations that lead to increased RAS/RAF/MEK/ERK signaling and are associated with intellectual disability, epilepsy, and ADHD. We do not fully understand how distinct neuronal subtypes are affected in these syndromes. Here, we show that increased MEK signaling in developing mice promotes the embryonic death of a specific subset of cortical inhibitory neurons that express parvalbumin. Surviving mutant parvalbumin neurons also show significant changes in crucial maturation processes, which coincide with increased seizure susceptibility and profound deficits in behavioral inhibition. These data suggest that deficits in inhibitory circuit development contribute to RASopathy neuropathogenesis and indicate that therapeutic strategies targeting inhibitory interneuron dysfunction may be beneficial for these individuals.

neuroscience↗