Biology subjects

Hewitt, L. T.

Publications and source records attributed to Hewitt, L. T..

5 recordsLinked to original sources

bioRxiv2024

Social odors drive hippocampal CA2 place cell responses to social stimuli

Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.

neuroscience↗

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

Higher hyperpolarization activated current (Ih) in a subpopulation of hippocampal stratum oriens CA1 interneurons in Fragile X mice.

Fragile X syndrome is the most common inherited form of intellectual disability and the leading monogenetic cause of autism. Studies in mouse models of autism spectrum disorders, including the Fmr1 knockout (FX) mouse, suggest that abnormal inhibition in hippocampal circuits contributes to behavioral phenotypes. We and others previously identified changes in multiple voltage-gated ion channels in hippocampal excitatory pyramidal neurons in FX mice. Whether the intrinsic properties of hippocampal inhibitory interneurons are altered in FX remains largely unknown. We made whole-cell current clamp recordings from three types of interneurons in stratum oriens of the hippocampus: fast-spiking (FS) cells and two classes of low threshold spiking cells, oriens-lacunosum moleculare (OLM) and low-threshold high Ih (LTH) neurons. We found that in FX mice, input resistance and action potential firing frequency were lower in LTH, but not FS or OLM, interneurons compared to wild type. Bath application of the h-channel blocker ZD7288 had a larger effect on input resistance in FX LTH cells and normalized input resistance between wild type and FX LTH cells, suggesting a greater contribution of Ih in FX LTH cells. In agreement, voltage clamp recordings showed that Ih was higher in FX LTH cells compared to wild type. Our results suggest that the intrinsic excitability of LTH inhibitory interneurons may contribute to altered inhibition in the hippocampus of FX mice. Significance statementChanges in the balance between excitation and inhibition underlie many neurodevelopmental disorders. Changes in several voltage-gated ion channels, which contribute to altered intrinsic excitability, were previously identified in excitatory hippocampal neurons in the Fmr1 mouse model of Fragile X syndrome. In this paper we use physiological and biochemical approaches to investigate the intrinsic excitability of inhibitory interneurons in hippocampal area CA1 of the Fragile X mouse. We found that higher Ih lowers the intrinsic excitability of one specific type of interneuron. This study highlights how changes to voltage-gated ion channels in specific neuronal populations may contribute to the altered excitatory/inhibitory balance in Fragile X syndrome.

neuroscience↗

bioRxiv2021

High and low expression of the hyperpolarization activated current (Ih) in mouse CA1 stratum oriens interneurons.

Inhibitory interneurons are among the most diverse cell types in the brain; the hippocampus itself contains more than 28 different inhibitory interneurons. Interneurons are typically classified using a combination of physiological, morphological and biochemical observations. One broad separator is action potential firing: low threshold, regular spiking vs. higher threshold, fast spiking. We found that spike frequency adaptation (SFA) was highly heterogeneous in low threshold interneurons in the mouse stratum oriens region of area CA1. Analysis with a k-means clustering algorithm parsed the data set into two distinct clusters based on a constellation of physiological parameters and reliably sorted strong and weak SFA cells into different groups. Interneurons with strong SFA fired fewer action potentials across a range of current inputs and had lower input resistance compared to cells with weak SFA. Strong SFA cells also had higher sag and rebound in response to hyperpolarizing current injections. Morphological analysis shows no difference between the two cell types and the cell types did not segregate along the dorsal-ventral axis of the hippocampus. Strong and weak SFA cells were labeled in hippocampal slices from SST:cre Ai14 mice suggesting both cells express somatostatin. Voltage-clamp recordings showed hyperpolarization activated current Ih was significantly larger in strong SFA cells compared to weak SFA cells. We suggest that the strong SFA cell represents a previously uncharacterized type of CA1 stratum oriens interneuron. Due to the combination of physiological parameters of these cells, we will refer to them as Low Threshold High Ih (LTH) cells. Key PointsO_LISpike frequency adaptation (SFA) was highly variable among stratum oriens interneurons C_LIO_LIAdapting stratum oriens interneurons were separated into two cell groups using multiple subthreshold and action potential parameters by cluster analysis C_LIO_LICells with strong SFA fired fewer action potentials for a given current injection, had lower input resistance and more sag and rebound compared to weak SFA cells C_LIO_LIThe physiological differences were not correlated with neuron morphology, location in stratum oriens, or anatomical location along the dorsal-ventral axis of the hippocampus C_LIO_LIVoltage-clamp recordings revealed that strong SFA cells had higher density of the hyperpolarization activated current Ih compared to weak SFA cells C_LI

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↗