Biology subjects

Blatt, G. J.

Publications and source records attributed to Blatt, G. J..

4 recordsLinked to original sources

bioRxiv2024

Developmental transformations of Purkinje cells tracked by DNA electrokinetic mobility

Brain development relies on orchestrated placement and timing of neurogenesis in progenitor zones to produce the expansive cellular diversity of the brain. We took advantage of bioelectric interactions between DNA and embryonic tissue to perform "stereo-tracking", a developmental targeting strategy that differentially labels cells positioned at different depths within intact progenitor zones. This three-dimensional labeling was achieved by delivery of plasmids with distinct electrokinetic mobilities into neural progenitor zones in utero. We applied stereo-tracking with light sheet imaging in the cerebellum and identified that Purkinje cells follow embryonically committed developmental trajectories linking distinct progenitor zone fields to the topography of the mature cerebellar cortex. In the process of stereo-tracking, we identified a previously unreported subcellular structure on the axon initial segment of Purkinje cells. These structures, we termed "axon bubbles", are developmentally timed and differentially labeled by lipid-modified proteins. Our findings demonstrate key rules that orchestrate the stereotyped transformations from fetal progenitors into mature networks of neuronal circuits, and demonstrate the potential of progenitor zone stereo-tracking to reveal new biology within intact developing systems.

neuroscience↗

bioRxiv2022

Region-specific alterations of perineuronal net expression in postmortem autism brain tissue

Genetic variance in ASD is often associated with mechanisms that broadly fall into the category of neuroplasticity. Parvalbumin positive neurons and their surrounding perineuronal nets (PNNs) are important factors in critical period plasticity and have both been implicated in ASD. PNNs are found in high density within output structures of the cerebellum and basal ganglia, two regions that are densely connected to many other brain areas and have the potential to participate in the diverse array of symptoms present in an ASD diagnosis. The dentate nucleus and globus pallidus were therefore assessed for differences in PNN expression in human postmortem ASD brain tissue. While Purkinje cell loss is a consistent neuropathological finding in ASD, in this cohort, the Purkinje cell targets within the dentate nucleus did not show differences in number of cells with or without a PNN. However, the density of parvalbumin positive neurons with a PNN were significantly reduced in the globus pallidus internus and externus of ASD cases, which was not dependent on seizure status. It is unclear whether these alterations manifest during development or are a consequence of activity-dependent mechanisms that lead to altered network dynamics later in life.

neuroscience↗

bioRxiv2021

Differential chemoarchitecture of Purkinje neurons contributes to intrinsic firing properties

Purkinje cells (PCs) are central to cerebellar information coding and appreciation for the diversity of their firing patterns and molecular profiles is growing. Heterogeneous subpopulations of PCs have been identified that display differences in intrinsic firing properties without clear mechanistic insight into what underlies the divergence in firing parameters. Although long used as a general PC marker, we report that the calcium binding protein parvalbumin labels a subpopulation of PCs with a conserved distribution pattern across the animals examined. We trained a convolutional neural network to recognize the parvalbumin-positive subtype and create maps of whole cerebellar distribution and find that PCs within these areas have differences in spontaneous firing that can be modified by altering calcium buffer content. These subtypes also show differential responses to potassium and calcium channel blockade, suggesting a mechanistic role for variability in PC intrinsic firing through differences in ion channel composition. It is proposed that ion channels drive the diversity in PC intrinsic firing phenotype and parvalbumin calcium buffering provides capacity for the highest firing rates observed. These findings open new avenues for detailed classification of PC subtypes.

neuroscience↗

bioRxiv2020

Altered Expression of Cadherin-8 and Cadherin-11 in Neural Circuit Development: Implications for Autism

Autism spectrum disorder (ASD) is a neurological condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue. In mice, expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in the cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Both cadherins were expressed in synaptic compartments but only cadherin-8 associated with the excitatory synaptic marker neuroligin-1. Induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed upregulated CDH8 expression levels while CDH11 expression levels were downregulated. We used Cdh11 knockout mice of both sexes to analyze the function of cadherin-11, which could help explain phenotypes observed in autism. Cdh11-/- hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in human tissue, levels of cadherin-8 were significantly elevated in Cdh11 knockout brains. Additionally, excitatory synaptic markers neuroligin-1 and PSD-95 were both increased. Together, these results strongly suggest that cadherin-11 is involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-11 may contribute to the etiology of autism. Significance StatementAutism is a neurodevelopmental condition with high genetic and phenotypic heterogeneity. Multiple genes have been implicated in autism, including the cadherin superfamily of adhesion molecules, cadherin-8 and cadherin-11. This study first characterizes the expression profiles of cadherin-8 and cadherin-11 to understand the potential roles they play in the development of neurons. The study further describes novel contributions of cadherin-11 in neural circuit formation. Loss of cadherin-11 in mice results in altered levels of several synaptic proteins, including PSD-95, neuroligin-1, and cadherin-8, and changes the morphology and activity of excitatory neurons. The levels of cadherin-8 and cadherin-11 in human cells of autistic individuals are both altered, strengthening the hypothesis that these two cadherins may involve in aspects of autism etiology.

neuroscience↗