Biology subjects

Henkelman, M.

Publications and source records attributed to Henkelman, M..

4 recordsLinked to original sources

bioRxiv2021

Why do hippocampal mossy cells matter? It depends on the frequency and context.

The discrimination of similar episodes and places, and their representation as distinct memories, depend on a process called pattern separation that relies on the circuitry of the hippocampal dentate gyrus (DG). Mossy cells (MCs) are key neurons in the circuitry, but how they influence DG network dynamics, function, and seizure risk has not been fully elucidated. We found the net impact of MCs was inhibitory at physiological frequencies connected with learning and behaviour, and their absence associated with deficits in pattern separation and spatial memory; at higher frequencies, their net impact was excitatory, and their absence protected against seizures. Thus, MCs influence DG outputs in a highly dynamic manner that varies with frequency and context. One-Sentence SummaryHippocampal mossy cells are required for learning and memory; but their absence protects against seizures.

neuroscience↗

bioRxiv2019

Tmod2 is a regulator of cocaine responses through control of striatal and cortical excitability, and drug-induced plasticity

Drugs of abuse induce neuroadaptations, including synaptic plasticity, that are critical for transition to addiction, and genes and pathways that regulate these neuroadaptations are potential therapeutic targets. Tropomodulin 2 (Tmod2) is an actin-regulating gene that plays an important role in synapse maturation and dendritic arborization and has been implicated in substance-abuse and intellectual disability in humans. Here we mine the KOMP2 data and find that Tmod2 knockout mice show emotionality phenotypes that are predictive of addiction vulnerability. Detailed addiction phenotyping showed that Tmod2 deletion does not affect the acute locomotor response to cocaine administration. However, sensitized locomotor responses are highly attenuated in these knockouts, indicating perturbed drug-induced plasticity. In addition, Tmod2 mutant animals do not self-administer cocaine indicating lack of hedonic responses to cocaine. Whole brain MR imaging shows differences in brain volume across multiple regions although transcriptomic experiments did not reveal perturbations in gene co-expression networks. Detailed electrophysiological characterization of Tmod2 KO neurons, showed increased spontaneous firing rate of early postnatal and adult cortical and striatal neurons. Cocaine-induced synaptic plasticity that is critical for sensitization is either missing or reciprocal in Tmod2 KO nucleus accumbens shell medium spiny neurons, providing a mechanistic explanation of the cocaine response phenotypes. Combined, these data provide compelling evidence that Tmod2 is a major regulator of plasticity in the mesolimbic system and regulates the reinforcing and addictive properties of cocaine.\n\nSignificance statementWe identify, characterize, and establish tropomodulin 2 (Tmod2), an actin-regulating gene exclusively expressed in neurons, as an important regulator of addiction-related phenotypes. We show that Tmod2, knockout mice (Tmod2 KO) exhibit phenotypes that are predictive of addiction. In detailed addiction phenotyping, we find the Tmod2 regulates cocaine sensitization and self-administration. We explore anatomical, transcriptional, electrophysiological mechanisms of this regulation. Combined these studies provide compelling evidence that Tmod2 is critical for synaptic plasticity necessary for transition to addiction.

neuroscience↗

bioRxiv2018

Aberrant mast cell activation promotes chronic recurrent multifocal osteomyelitis

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease. While some patients exhibit bone lesions at single sites, most patients develop chronically active or recurrent bone inflammation at multiple sites, and are then diagnosed with recurrent multifocal osteomyelitis (CRMO). Chronic multifocal osteomyelitis (CMO) mice develop IL-1{beta}-driven sterile bone lesions reminscent of severe CRMO. Mechanistically, CMO disease arises due to loss of PSTPIP2, a negative regulator of macrophages, osteoclasts and neutrophils. The goal of this study was to evaluate the potential involvement of mast cells in CMO/CRMO disease pathophysiology. Here, we show that mast cells accumulate in the inflamed tissues from CMO mice, and mast cell protease Mcpt1 was detected in the peripheral blood. The role of mast cells in CMO disease was investigated using a transgenic model of connective tissue mast cell depletion (Mcpt5-Cre:Rosa26-Stopfl/fl-DTa) that was crossed with CMO mice. The resulting CMO/MC-mice showed a significant delay in disease onset compared to age-matched CMO mice. At 5-6 months of age, CMO/MC- mice had fewer bone lesions and immune infiltration in the popliteal lymph nodes that drain the affected tail and paw tissues. To test the relevance of mast cells to human CRMO, we tested serum samples from a cohort of healthy controls or CRMO patients at diagnosis. Interestingly, mast cell chymase was elevated in CRMO patients as well as patients with oligoclonal juvenile arthritis. Tryptase-positive mast cells were also detected in bone lesions from CRMO patients as well as patients with bacterial osteomyelitis. Taken together, our results identify mast cells as cellular contributors to bone inflammation in CMO/CRMO. Observations of this study promise potential for mast cells and derived mediators as future biomarkers and/or therapeutic targets.

immunology↗

bioRxiv2017

Cardiac enriched BAF chromatin remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

How gene networks controlling organ-specific properties are modulated by chromatin remodeling complexes is not well understood. Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex. Its role throughout heart development is not fully understood. We show that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes results in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen we identify MYOCD as a BAF60c interacting factor; we show that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.

developmental biology↗