Genetic variance in autism spectrum disorder (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 (DN) and globus pallidus (GP) 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 DN 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 GP 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.
Autism spectrum disorder (ASD) is behaviorally defined and diagnosed by delayed and/or impeded language, stereotyped repetitive behaviors and difficulties with social interactions. Additionally, ...there are disruptions in motor processing, which includes the intent to execute movements, interrupted/inhibited action chain sequences, impaired execution of speech and repetitive motor behaviors. Cortical loops through basal ganglia (BG) structures are known to play critical roles in the typical functioning of these actions. Specifically, corticostriate projections to the dorsal striatum (caudate and putamen) convey abundant input from motor, cognitive and limbic cortices and subsequently project to other BG structures. Excitatory dopamine (DA) type 1 receptors are predominantly expressed on GABAergic medium spiny neurons (MSNs) in the dorsal striatum as part of the “direct pathway” to GPi and SNpr whereas inhibitory DA type 2 receptors are predominantly expressed on MSNs that primarily project to GPe. This study aimed to better understand how this circuitry may be altered in ASD, especially with regard to the neurochemical modulation of GABAergic MSNs within the two major BG pathways. We utilized two classical methods to analyze the postmortem BG in ASD in comparison to neurotypical cases: ligand binding autoradiography to quantify densities of GABA-A, GABA-B, 5-HT2 and DA type 1 and 2 receptors and in situ hybridization histochemistry (ISHH) to quantify mRNA for D1, D2 receptors and three key GABAergic subunits (alpha1, beta2, gamma2), as well as the GABA synthesizing enzymes (GAD65/67). Results demonstrated significant increases in D2 mRNA within MSNs in both the caudate and putamen, which was further verified by proenkephalin mRNA that is co-expressed with the D2 receptor in indirect pathway MSNs. In contrast, all other GABAergic, serotonergic and dopaminergic markers in the dorsal striatum had comparable labeling densities. These results indicate alterations in the indirect pathway of the BG, with possible implications for the execution of competing motor programs and E/I imbalance in the direct/indirect motor feedback pathways through thalamic and motor cortical areas. Results also provide insights regarding the efficacy of FDA approved drugs used to treat individuals with ASD acting on specific DA and 5-HT receptor subtypes.
Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD), however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been ...primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology.
At present, the neuronal mechanisms underlying the diagnosis of autism spectrum disorder (ASD) have not been established. However, studies from human postmortem ASD brains have consistently revealed ...disruptions in cerebellar circuitry, specifically reductions in Purkinje cell (PC) number and size. Alterations in cerebellar circuitry would have important implications for information processing within the cerebellum and affect a wide range of human motor and non-motor behaviors. Laser capture microdissection was performed to obtain pure PC populations from a cohort of postmortem control and ASD cases and transcriptional profiles were compared. The 427 differentially expressed genes were enriched for gene ontology biological processes related to developmental organization/connectivity, extracellular matrix organization, calcium ion response, immune function and PC signaling alterations. Given the complexity of PCs and their far-ranging roles in response to sensory stimuli and motor function regulation, understanding transcriptional differences in this subset of cerebellar cells in ASD may inform on convergent pathways that impact neuronal function.
Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been ...primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology.
Dr. Deepak “Dee” Pandya spent his career as an internal medicine physician as well as in his respective laboratories at the Bedford, Massachusetts Veterans Administration Hospital and at Boston ...University School of Medicine. His achievements mapping out the cytoarchitecture and connectivity of areas all over the nonhuman primate brain and small mammals are unparalleled. Dee made numerous discoveries and created painstakingly detailed reports, which impacted the field of neuroanatomy and expanded our perceptions of the many diverse inputs and suggestive functions of specific brain regions. The “old school” methods employed from microscopic work to detailed analyses yielded a product that was accurate and exciting all at the same time. We will all miss Dee's smile and tender manner, but more so, we will miss his wonderful and patient mentorship during the precious time we all spent with him. His mentorship resulted in all of his trainees becoming better scientists and left us with the understanding that people like Dee only come by once in a lifetime. In this tribute article for this special issue in the Journal of Comparative Neurology (JCN), the authors describe some of the tedious methods that were used to present our work as a way to provide insight into the extraordinary time and effort it took to produce and publish our articles with Dee in JCN. Dee's work with his colleagues set the stage for more modern methods of counting and mapping neuronal populations presented here, paving the way for such technologies as artificial intelligence and light sheet imaging to advance the field forward to reach new and exciting discoveries.
In this tribute article, we describe the legacy of Dr. Deepak Pandya on neuroanatomy and how he influenced our research. We provide examples of tracing with India ink and how methods have evolved to tracking neurons and their connections with artificial intelligence and whole brain imaging.
The cover image is based on the Research Article India ink to 3D imaging: The legacy of Dr. Deepak “Dee” N. Pandya and his influence on generations of neuroanatomists by Gene J. Blatt et al., ...https://doi.org/10.1002/cne.25551.
As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to determine whether targets for SSRIs are differentially affected in three ...cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n = 14–19 per group), saturation ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex, and fusiform gyrus (FG). Specific binding to the 5‐HT transporter (5‐HTT) as well as to 5‐HT2 and 1A receptors (5‐HT₂, 5‐HT1A) was quantified in superficial and deep layers of each region using the ligands 3H‐citalopram (5‐HTT), 3H‐ketanserin (5‐HT2), and 3H‐8‐OH‐DPAT (5‐HT1A). A Welch’s t‐test was utilized to compare receptor densities (Bmax), revealing a statistically significant decrease in 5‐HTT within the ACC of the entire autism cohort. There was also a decrease in 5‐HT2 receptor density in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of Bmax values plotted against age, shows a significantly lower intercept for 5‐HTT in autism (p = 0.025). 5‐HT₂ density increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p = 0.032). This suggests a deficit in 5‐HTT within the ACC in individuals with autism, while decreases in 5‐HT₂ density are age‐dependent. There were no differences in receptor densities in the posterior cingulate cortex or FG in autism and no differences in ligand affinity (KD) across all regions and ligands examined.
Although selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, several studies show variable efficacy with SSRI use. Some of this variability may be a result of differential expression of serotonin receptors across individuals. The objective of this study was to determine differences in density and/or affinity of the serotonin transporter (5‐HTT), serotonin 2 receptor (5‐HT2) and serotonin 1A receptor (5‐HT1A) between autism and neurotypical individuals through saturation binding assays within three cortical areas. Our findings support the growing evidence for caution when administering SSRIs to children, while adults may benefit from these treatments.
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