Biology subjects

Holter, M. C.

Publications and source records attributed to Holter, M. C..

3 recordsLinked to original sources

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↗

bioRxiv2020

Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity

Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs) which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes in unknown. ChIs represent less than 1% of the accumbens neuronal population yet are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine seeking behavior. Using chemogenetics transgenic rats that express Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bi-directionally manipulated prior to cue-induced reinstatement. Following nicotine self-administration and extinction training, ChIs were activated or inhibited prior to a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / N-Methyl-D-Aspartate (NMDA) (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, whereas activation of ChIs had no effect, demonstrating that ChI inhibition prevents transient synaptic potentiation (t-SP) associated with cue-induced nicotine seeking. To assess potential underlying mechanisms, accumbens 4{beta}2- and 7-containing nicotinic ACh receptors (nAChRs) were pharmacologically inhibited and MSN synaptic morphology was assessed following reinstatement. Inhibition of both nAChR subtypes prevented cue-induced nicotine seeking and t-SP (measured via changes in spine head diameter). Together, these results demonstrate that these neurons mediate cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.

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↗