Biology subjects

Richardson, B. D.

Publications and source records attributed to Richardson, B. D..

4 recordsLinked to original sources

bioRxiv2025

Shank3 establishes AMPA receptor subunit composition at cerebellar mossy fiber-granule cell synapses and shapes regional microglia activation.

Mutations in Shank3 are the primary genetic cause of Phelan-McDermid Syndrome (PMS), a neurodevelopmental disorder frequently comorbid with autism spectrum disorder (ASD). As a key scaffolding protein in the postsynaptic site, SHANK3 is critical for excitatory glutamatergic synapse function by interacting with AMPARs, NMDARs, and mGluRs. While Shank3 deficiency has been extensively studied in forebrain regions, its role in the cerebellum, a brain area increasingly implicated in ASD pathobiology, remains comparatively underexplored. Cerebellar granule cells (CGCs) exhibit high Shank3 expression. However, its role in cerebellar glutamatergic synapses is poorly understood. This study aims to investigate how Shank3 loss affects mossy fiber-CGC glutamatergic synaptic function. Whole-cell patch clamp electrophysiological recordings from CGCs in ex vivo cerebellar brain slices from adult (4-6 months old) wild type (WT) and homozygous Shank3{Delta}ex4-22 KO were performed to record miniature, evoked, and glutamate uncaged responses. Similarly, the current-voltage (I-V) relationship was analyzed with intracellular spermine and pharmacological validation of calcium-permeable AMPARs (CP-AMPARs) was done by IEM-1460. Immunofluorescence staining was performed for microglia using IBA1 labeling. We found a significant increase in mEPSC amplitude and AMPAR-mediated response to glutamate uncaging, which indicates that the loss of Shank3 enhances postsynaptic AMPAR function. Furthermore, the KO group showed faster AMPAR decay kinetics, inward rectification, and increased sensitivity to IEM-1460, suggesting that a high proportion of CP-AMPARs with distinct biophysical properties are present at the MF-CGC synapse. Furthermore, KO mice showed less ramified microglia suggesting the possible presence of activated microglia in the cerebellar cortex. Together, these findings highlight a critical role of Shank3 in maintaining the balance between CP- and CI-AMPARs at the MF-CGC synapse, which is essential for synapse maturation and proper cerebellar circuitry function. Dysregulation of this balance, with possible presence of activated microglia in the cerebellum, may underscore cerebellar-related behavioral deficits in Shank3 KO mice and may suggest a potential mechanism contributing to ASD pathophysiology.

neuroscience↗

bioRxiv2024

Early life stress induced sex-specific changes in behavior is paralleled by altered locus coeruleus physiology in BALB/cJ mice

Adverse childhood experiences have been associated with many neurodevelopmental and affective disorders including attention deficit hyperactivity disorder and generalized anxiety disorder, with more exposures increasing negative risks. Sex and genetic background are biological variables involved in adverse psychiatric outcomes due to early life trauma. Females in general have an increased prevalence of stress-related psychopathologies beginning after adolescence, indicative of the adolescent time period being a female-specific sensitive period. To understand the underlying neuronal components responsible for this relationship between genetic background, sex, stress/trauma, and cognitive/affective behaviors, we assessed behavioral and neuronal changes in a novel animal model of early life stress exposure. Male and female BALB/cJ mice that express elevated basal anxiety-like behaviors and differences in monoamine associated genes, were exposed to an early life variable stress protocol that combined deprivation in early life with unpredictability in adolescence. Stress exposure produced hyperlocomotion and attention (5 choice serial reaction time task) in male and female mice along with female-specific increased anxiety-like behavior. These behavioral changes were paralleled by reduced excitability of locus coeruleus (LC) neurons, due to resting membrane potential hyperpolarization in males and a female specific increase in action potential delay time. These data describe a novel interaction between sex, genetic background, and early life stress that results in behavioral changes in clinically-relevant domains and potential underlying mechanistic lasting changes in physiological properties of neurons in the LC. HIGHLIGHTSO_LIBALB/cJ mice exposed to early life stress are hyperactive in adolescence and displayed attention deficits in adulthood. C_LIO_LIOnly female BALB/cJ mice develop increased anxiety in adolescence after early life stress. C_LIO_LIEarly life stress causes reduced excitability of locus coeruleus neurons in BALB/cJ mice. C_LIO_LIOnly locus coeruleus neurons from female BALB/cJ mice exposed to early life stress displayed an increase in action potential delay time upon depolarization. C_LI

neuroscience↗

bioRxiv2023

Early life stress induces sex-specific changes in behavior and parallel locus coeruleus neuron excitability

Many psychiatric disorders are associated with specific risk factors, including biological sex, chronic stress, and adversity in childhood, but mechanisms underlying these relationships are unknown. The locus coeruleus (LC) is a brain area that contains adrenergic norepinephrine (NE)-releasing neurons with established sex differences in excitability and stress sensitivity. To understand how adversity in early life affects cognitive/affective behavior and LC physiology, we exposed C57BL/6J mice to a dual-phase (early development and adolescence) early life variable stress (ELVS) paradigm and assessed behavior and LC physiology in early adulthood. ELVS caused females, but not males, to display increased novel environment exploration and reduced preference for sucrose. In addition, ELVS caused elevated activity in a familiar environment, modest deficits in Y-maze performance, and altered attention in an operant task, regardless of sex. A reduction in LC neuron excitability, partly due to an increase in action potential delay time, was also found only in female mice exposed to ELVS, paralleling robust behavioral changes. Pharmacological compensation of these changes in LC activity with reboxetine corrected some ELVS-induced behavioral changes. CRF-induced changes in LC neuron activity were also mediated by different preferential signaling pathways in male and female mice, a potential mechanism for lasting sex-specific changes in LC physiology in response to ELVS. Through this animal model of early life stress, we identified sex differences in behavior and parallel changes in LC neuron excitability and CRF sensitivity, identifying mechanisms involved in determining how stress and sex interact to cause LC activity dysregulation and related behavioral changes.

neuroscience↗

bioRxiv2020

CB1 receptor signaling modulates amygdalar plasticity during context-cocaine memory reconsolidation to promote subsequent cocaine seeking

Contextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental rat model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, I.P.) during memory reconsolidation alters (a) subsequent drug context-induced cocaine-seeking behavior, as well as (b) cellular adaptations and (c) excitatory synaptic physiology in the basolateral amygdala (BLA). Systemic CB1R antagonism - during, but not after, cocaine-memory reconsolidation - reduced drug context-induced cocaine-seeking behavior three days, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene expression and changes in BLA -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous excitatory post-synaptic current frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA during cocaine-memory reconsolidation, thereby facilitating cocaine-memory maintenance. These findings identify the CB1R as a potential therapeutic target for relapse prevention. SIGNIFICANCE STATEMENTDrug relapse can be triggered by the retrieval of context-drug memories upon re-exposure to a drug-associated environment. Context-drug associative memories become destabilized upon retrieval and must be reconsolidated into long-term memory stores in order to persist. Hence, targeted interference with memory reconsolidation can weaken maladaptive context-drug memories and reduce the propensity for drug relapse. Our findings indicate that cannabinoid type 1 receptor (CB1R) signaling is critical for context-cocaine memory reconsolidation and subsequent drug context-induced reinstatement of cocaine-seeking behavior. Furthermore, cocaine-memory reconsolidation is associated with CB1R-dependent immediate-early gene expression and changes in excitatory synaptic proteins and physiology in the basolateral amygdala. Together, our findings provide initial support for CB1R as a potential therapeutic target for relapse prevention.

neuroscience↗