• Differential chemoarchitecture of Purkinje neurons within cerebellar lobules contributes to intrinsic plasticity: Significance for autism spectrum disorders

      Brandenburg, Cheryl; Blatt, Gene J.; Keller, Asaf; 0000-0002-9370-2313 (2020)
      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 insights into what underlies the divergence in firing parameters. Although long used as a general PC marker, here it is reported that the calcium binding protein parvalbumin labels a subpopulation of PCs with a conserved distribution pattern, similar to aldolase C. A convolutional neural network was trained to recognize the parvalbumin-positive subtype and create maps of whole cerebellar distribution. PCs within these areas have differences in spontaneous firing that can be modified by altering calcium buffer content, which implicates parvalbumin in setting the spike rate and contributing to burst-pause behavior. These subtypes also show differential responses to potassium and calcium channel blockade, suggesting a mechanistic role for variability in PC intrinsic firing. These findings open new avenues for detailed classification of PC subtypes and prompt further investigation into determining which subtype(s) are affected by the reported PC decreases within human postmortem autism brain tissue. Part 2 explores serotonin, GABA and dopamine in cortical regions and the basal ganglia in the human postmortem autism brain to quantify differences in receptor subtypes.
    • Identification and Characterization of a Sensitive Period in Cerebellar Development

      Hoffman, Jessica Frances; McCarthy, Margaret M., 1958- (2014)
      The cerebellum, a brain region long established to have a role in motor control, has begun to be appreciated for its involvement in sensory perception and higher cognitive functions. Our previous research has found evidence for a prostaglandin E2 (PGE2)-estradiol signaling pathway in the rat cerebellum, and decreasing PGE2 synthesis in the second postnatal week results in excessive growth of Purkinje cell dendritic trees and abnormal sensory and social behavior. Here we confirm that this signaling pathway has a role in Purkinje cell development by demonstrating that during the second postnatal week, inducing an increase in PGE2 synthesis by treatment with lipopolysaccharide (LPS) increases aromatase activity and estradiol synthesis and stunts Purkinje cell dendrite growth. Additionally, we report that inflammation induced by LPS or mimicked by directly injecting PGE2 disrupts social and cognitive behaviors without affecting normal motor control. Specifically, in males and females, both LPS and PGE2 increase total object exploration, which we interpret as increased perseverance of interest with objects. LPS and PGE2 also decrease social play behavior, but only in males. These changes in Purkinje cell development and in behavior can be prevented with the aromatase inhibitor, formestane, suggesting a link between estradiol, cerebellar development, and its role in higher cognitive functioning. Further, these biochemical, morphological, and behavioral changes are only seen when inflammation occurs within the second postnatal week, not in the first or third. Autism spectrum disorder and Schizophrenia are neurodevelopmental diseases with complex and poorly understood genetic and environmental components. Both have been associated with cerebellar pathology and early life inflammation, particularly the developmental period between in utero and early childhood - a very similar time frame to the sensitive period we describe. Our findings suggest that the second postnatal week of life in the rat is a developmental period in which fever and inflammation may increase the risk for neurodevelopmental disorders by altering cerebellar development.
    • Regulation of cerebellar estradiol synthesis and Purkinje cell morphology by prostaglandins: Implications for neurodevelopmental disease

      Dean, Shannon Lee; McCarthy, Margaret M., 1958- (2009)
      Cerebellar pathology occurs in autism and schizophrenia, complex diseases with genetic and environmental origins. The genesis of these diseases is still not understood but inflammation in utero or early in childhood is an important environmental risk factor. Prostaglandin E2 (PGE2) is the key regulator of inflammation and fever, and is potently reduced by COX inhibitors, including over-the-counter medications. However, prostaglandins play other roles in normal physiology. In some brain regions such as the preoptic area, prostaglandins play an important role in normal brain development, creating enduring changes in synaptic patterning. Whether prostaglandins are also important factors in cerebellar development is unknown but worth investigating. Cerebellar development in rats is well studied. We demonstrate that inhibiting prostaglandin production via COX inhibitors increases dendrite length and spine number on Purkinje cells in the rat cerebellum during the early postnatal period, and that the prostaglandin PGE2 decreases markers of dendritic spines in vitro during an equivalent time period. We hypothesized that prostaglandins and estradiol are part of a common pathway in the cerebellum as they are in the preoptic area. We report that that PGE2 stimulates the production of estradiol in the immature cerebellum via an upregulation of the enzyme aromatase, and that treatment with estradiol reduces dendritic growth and synaptogenesis of cerebellar Purkinje cells. Given the effects of prostaglandins during cerebellar development and the cerebellar pathology found in diseases such as autism and schizophrenia, we hypothesized that blocking the normal production of prostaglandins with COX inhibitors would alter social behavior and sensory perception, and would lead to enduring alterations in cerebellar morphology. We found a reduction in cerebellar synapses and overall volume in juvenile rats. This later phase is associated with reduced social play behavior and heightened somatosensory response in males alone, a behavioral pattern reminiscent of patients with autism or schizophrenia. We conclude that prostaglandins are important players in cerebellar development and in the development of normal social and sensory behavior. Understanding the role prostaglandins play in development may give us insight into complex human neurodevelopmental diseases.