The results suggest that adolescent risperidone treatment induces lasting transcriptomic and functional changes associated with altered excitatory-inhibitory neuronal interactions that may underline cognitive and behavioral dysregulations.
Abstract
Since the introduction of second-generation antipsychotics, antipsychotics have been increasingly prescribed for children and adolescents, raising concerns about their long-term impact on neurodevelopment. Antipsychotics block dopaminergic and serotonergic receptors, potentially disrupting the maturation of neurocognitive processes, which is a public health concern. Previous studies have reported that adolescent antipsychotic treatment can cause persistent neurocognitive dysfunction in rodents, yet the neurobiological underpinnings remain unknown. To address this, we administered risperidone, a commonly used antipsychotic, to C57BL/6 mice during adolescence (3 to 6 weeks of age) and examined behavioral and neurobiological outcomes nine weeks post-treatment. Risperidone-treated mice exhibited subtle deficits in behavioral correlates of anxiety-like behavior. In vivo, two-photon calcium imaging of cortical neurons revealed a remarkable increase in the amplitude of calcium events with subtle sex-specific changes in the frequency, consistent with increased neuronal excitability. Single-nucleus RNA-sequencing (snRNA-seq) analyses showed widespread reductions in transcripts for voltage-sensitive and inwardly rectifying potassium channels in both pyramidal neurons and interneurons. Additionally, both cell types exhibited reduced Grin2a and Grin2b, as well as scaffolding proteins, indicative of weakened synaptic connectivity between excitatory and inhibitory neurons. Interestingly, we observed sex-dependent differences in the directionality of correlation between certain gene co-expression modules and risperidone treatment. Our results suggest that adolescent risperidone treatment induces lasting transcriptomic and functional changes associated with altered excitatory-inhibitory neuronal interactions that may underline cognitive and behavioral dysregulations.
Adolescence is a critical neurodevelopmental stage marked by heightened plasticity and vulnerability to environmental influences such as nicotine. Nicotine disrupts neural function via nicotinic acetylcholine receptors, leading to long-term impairments in reward processing, cognition, and emotional regulation. While links between adolescent nicotine exposure and adult psychiatric or cognitive deficits are established, the influence of genetics and sex remains unclear. We examined the long-term effects of adolescent nicotine exposure on adult behavior and neural circuitry in male and female C57BL/6J and DBA/2J mice. Nicotine (24 mg/kg/day) or saline was administered via subcutaneous osmotic minipumps from postnatal day 37 for 12 days. Behavioral assessments 4 weeks later included the elevated plus maze for anxiety-related behavior and the open field test for locomotor activity after acute nicotine (0.81 mg/kg). Resting-state functional magnetic resonance imaging evaluated brain connectivity changes. Nicotine exposure altered both behavior and functional connectivity, depending on strain and sex. Adult female C57BL/6J mice exposed to nicotine during adolescence had lower anxiety-like behavior and higher locomotor activity, along with increased striatal-hippocampal connectivity, suggesting adaptations either directly related to nicotine exposure or compensatory adaptations. In contrast, adult female DBA/2J mice exposed to nicotine during adolescence showed widespread disruptions in cortico-striatal-thalamic, polymodal association, and hippocampal networks critical for cognitive and emotional regulation. Overall, greater effects were seen in female mice. Findings reveal that adolescent nicotine exposure drives enduring, strain- and sex-dependent changes in adult brain connectivity and behavior. Considering genetics and sex is essential for tailoring interventions for nicotine addiction and its neuropsychiatric consequences.
Hayreddin Said Ünsal, Carlos Novoa, Nanyin Zhang et al.· Journal of Psychopharmacolog...· 0 citations
By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression by restoring neurotrophic signaling and dopaminergic function in the nucleus accumbens.
Kuan-Yin Tseng, Tung-Tai Kuo, P. Chang et al.· Journal of Parkinson's Disea...· 0 citations
First-line stimulant therapies for attention deficit hyperactivity disorder (ADHD) implicate the forebrain monoaminergic neurotransmitter systems of dopamine, noradrenaline and serotonin. However, there is no curative treatment. Investigation of neurochemical monoaminergic changes, followed by curative treatments, requires sub-type specific animal models. In a novel rat model of the hyperactive-impulsive and attentive subtype of ADHD, specific changes in forebrain monoamines, and correlations with ADHD-like hyperactivity/impulsivity after delayed reward, are unknown. To address this, we investigated the monoaminergic systems using high performance liquid chromatography at ~2 and 7 months-of-age. We correlated the latter findings with ADHD-like hyperactivity and impulsivity that was measured after delayed reward. We observed long-term effects on the serotonergic, dopaminergic and noradrenergic systems in the forebrain of ADHD-like, hyperactive-impulsive male rats exposed to repeated hypoxia during postnatal day 1-3, the equivalent of extreme prematurity. These long-term effects were strikingly correlated with ADHD-like impulsive, and mostly with ADHD-like hyperactive, behaviour after delayed reward. The correlation was stronger for the dopaminergic and noradrenergic systems and weaker for the serotonergic system. The findings strongly implicate the dopaminergic system in the right prefrontal cortex, the noradrenergic system in the left prefrontal cortex and the serotonergic system in the right posterior caudate-putamen in ADHD-like hyperactivity and ADHD-like impulsivity. Earlier reports of forebrain lateralisation and lifespan changes of monoamines and their metabolites, and of marked differences between the anterior versus posterior caudate-putamen bilaterally, were confirmed and extended. New treatments to collectively cure the neurochemical changes can now be investigated in this unique, ADHD-like subtype-specific animal model.
Sarah E. Kohe, Emma K. Gowing, S. Seo et al.· Neurobiology of Disease· 0 citations
It is demonstrated that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features.
Mathieu Thabault, Cloé Fernandes-Gomes, Cloé Alcaraz et al.· Neurobiology of Disease· 0 citations
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social behavior and cognition. Increasing evidence suggests that alterations in dopaminergic neurotransmission, including changes in dopamine transporter (DAT) function, may contribute to ASD-related behavioral abnormalities. This study investigated whether selective DAT inhibition during early postnatal development influences behavioral and molecular alterations in a rat model of ASD induced by prenatal exposure to sodium valproate (NaVP). Pregnant Wistar rats received NaVP (600mg/kg, i.p.) on gestational day 12.5. Male offspring were treated with the selective DAT inhibitor CE-123 (10mg/kg, i.p.) once daily from postnatal day (PND) 10 to 23. Behavioral assessments during adolescence (PND25-42) evaluated social interaction, recognition memory, spatial preference, anxiety-like behavior, locomotor activity, and aversive memory. DAT, dopamine D2 receptor, brain-derived neurotrophic factor (BDNF), and interleukin-1β (IL-1β) protein expression were assessed in selected brain regions. Prenatal NaVP exposure impaired social novelty discrimination, declarative, spatial, and aversive memory, reduced locomotor activity, and increased anxiety-like behavior. These behavioral alterations were accompanied by elevated DAT and dopamine D2 receptor expression. Early postnatal CE-123 treatment attenuated several ASD-like behavioral abnormalities, normalized DAT and dopamine D2 receptor expression, increased BDNF levels in the prefrontal cortex (PFC), and increased IL-1β expression, without inducing non-specific locomotor stimulation. Together, these findings demonstrate that early postnatal CE-123 treatment was associated with long-lasting behavioral improvements accompanied by alterations in dopaminergic markers and BDNF expression. Although these findings support a role for dopaminergic regulation and neuroplasticity in the observed behavioral effects, the underlying mechanisms require further investigation.
