medium-sized spiny neuron

Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. Therefore, we examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls. We found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression...

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits...

Monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters relevant for the availability of TH in neural cells, crucial for their proper development and function. Mutations in MCT8 or OATP1C1 result in severe disorders with dramatic movement disability related to alterations in basal ganglia motor circuits. Mapping the expression of MCT8/OATP1C1 in those circuits is necessary to explain their involvement in motor control...

Trinucleotide repeat disorders comprise ~20 severe, inherited, human neuromuscular and neurodegenerative disorders, which result from an abnormal expansion of repetitive sequences in the DNA. The most common of these, Huntington's disease (HD), results from expansion of the CAG repeat region in exon 1 of the HTT gene via an unknown mechanism. Since non-coding RNAs have been implicated in the initiation and progression of many diseases, herein we focused on a circular RNA (circRNA) molecule arising from non-canonical splicing (backsplicing) of HTT pre-mRNA...

Autism is characterized by atypical social communication and stereotyped behaviors. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1-2% of patients with autism and intellectual disability, but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterized the behavior of Shank3 Δ11/Δ11 mice from 3 to 12 months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and modification of socio-sexual interaction compared to wild-type littermates...

The mammalian striatum has long been considered a homogeneous entity. However, neuroanatomical and histochemical studies reveal that the striatum is much more heterogeneous than previously suspected. The caudate (Cd) and putamen (Pu) are composed of two chemical compartments: the matrix and the striosomes. Striatal interneurons have been classified into a variety of morphological and neurochemical subtypes. In this study, we compared the distribution of multiple neurochemical markers in the striatum of marmosets and described the morphology of different types of striatum interneurons...

An important factor that can modulate neuron properties is sex-specific hormone fluctuations, including the human menstrual cycle and rat estrous cycle in adult females. Considering the striatal brain regions, the nucleus accumbens (NAc) core, NAc shell, and caudate-putamen (CPu), the estrous cycle has previously been shown to impact relevant behaviors and disorders, neuromodulator action, and medium spiny neuron (MSN) electrophysiology. Whether the estrous cycle impacts MSN dendritic spine attributes has not yet been examined, even though MSN spines and glutamatergic synapse properties are sensitive to exogenously applied estradiol...

The serotonin 5-HT6 receptor (5-HT6 R) is a promising target to improve cognitive symptoms of psychiatric diseases of neurodevelopmental origin, such as autism spectrum disorders and schizophrenia. However, its expression and localization at different stages of brain development remain largely unknown, due to the lack of specific antibodies to detect endogenous 5-HT6 R. Here, we used transgenic mice expressing a GFP-tagged 5-HT6 R under the control of its endogenous promoter (Knock-in) as well as embryonic stem cells expressing the GFP-tagged receptor to extensively characterize its expression at cellular and subcellular levels during development...

BACKGROUND: Hydrocephalus is characterized by abnormal accumulation of cerebrospinal fluid in the cerebral ventricles and causes motor impairments. The mechanisms underlying the motor changes remain elusive. Enlargement of ventricles compresses the striatum of the basal ganglia, a group of nuclei involved in the subcortical motor circuit. Here, we used a kaolin-injection juvenile rat model to explore the effects of acute and chronic hydrocephalus, 1 and 5 weeks post-treatment, respectively on the three major neurotransmission pathways (glutamatergic, dopaminergic and cholinergic) in the striatum...

Huntington's disease (HD) is a fatal, hereditary neurodegenerative disorder that causes chorea, cognitive deficits, and psychiatric symptoms. It is characterized by accumulation of mutant Htt protein, which primarily impacts striatal medium-sized spiny neurons (MSNs), as well as cortical pyramidal neurons (CPNs), causing synapse loss and eventually cell death. Perturbed Ca2+ homeostasis is believed to play a major role in HD, as altered Ca2+ homeostasis often precedes striatal dysfunction and manifestation of HD symptoms...

Opioids are the most common medications for moderate to severe pain. Unfortunately, they also have addictive properties that have precipitated opioid misuse and the opioid epidemic. In the present study, we examined the effects of acute administration of oxycodone, a μ-opioid receptor (MOR) agonist, on Ca2+ transient activity of medium-sized spiny neurons (MSNs) in freely moving animals. Ca2+ imaging of MSNs in dopamine D1-Cre mice (expressing Cre predominantly in the direct pathway) or adenosine A2A-Cre mice (expressing Cre predominantly in the indirect pathway) was obtained with the aid of miniaturized microscopes (Miniscopes) and a genetically encoded Cre-dependent Ca2+ indicator (GCaMP6f)...

Antipsychotics share the common pharmacological feature of antagonizing the dopamine 2 receptor (D2R), which is abundant in the striatum and involved in both the therapeutic and side effects of this drug's class. The pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-sized spiny neurons (MSNs), leads to a plethora of molecular, cellular and behavioral adaptations, which are central in the action of antipsychotics. Here, we focused on the cell type-specific (D2R-MSNs) regulation of some striatal immediate early genes (IEGs), such as cFos, Arc and Zif268...

The striatum is primarily composed of two types of medium spiny neurons (MSNs) expressing either D1- or D2-type dopamine receptors. However, the fate determination of these two types of neurons is not fully understood. Here, we found that D1 MSNs undergo fate switching to D2 MSNs in the absence of Zfp503 . Furthermore, scRNA-seq revealed that the transcription factor Zfp503 affects the differentiation of these progenitor cells in the lateral ganglionic eminence (LGE). More importantly, we found that the transcription factors Sp8/9 , which are required for the differentiation of D2 MSNs, are repressed by Zfp503 ...

Striatal medium-sized spiny neurons express mRNA and protein of GPR55 receptors that stimulate neurotransmitter release; thus, GPR55 could be sent to nigral striatal projections, where it might modulate GABA release and motor behavior. Here we study the presence of GPR55 receptors at striato-nigral terminals, their modulation of GABA release, their signaling pathway, and their effect on motor activity. By double immunohistochemistry, we found the colocation of GPR55 protein and substance P in the dorsal striatum...

The caudate nucleus is described as a huge, subcortical grey mass in the forebrain known for its role in motor function and involved in a number of clinical syndromes. During ontogenesis, the caudate nucleus follows the curvature of the telencephalic vesicle, hence its curved shape. Its rostral portion referred to as the head, is far more voluminous than the body. AIMS: This study aimed to describe the different types and characteristics of neurons in the caudate nucleus of the brain of camel and human and compare these neurons with their counterparts in other species...

Huntington's disease (HD) is a fatal, hereditary neurodegenerative disorder that predominantly affects striatal medium-sized spiny neurons and cortical pyramidal neurons (CPNs). It has been proposed that perturbations in Ca2+ homeostasis could play a role in CPN alterations. To test this hypothesis, we used the R6/2 mouse model of juvenile HD at different stages of disease progression; presymptomatic, early symptomatic, and late symptomatic. We combined whole-cell patch clamp recordings of layer 2/3 CPNs with two-photon laser scanning microscopy to image somatic and dendritic Ca2+ transients associated with evoked action potentials (APs)...

BACKGROUND AND PURPOSE: Dopamine in the striatum plays a crucial role in reward processes and action selection. Dopamine signals are transduced by D1 and D2 dopamine receptors which trigger mirror effects through the cAMP/PKA signalling cascade in D1 and D2 medium-sized spiny neurones (MSNs). Phosphodiesterases (PDEs), which determine the profile of cAMP signals, are highly expressed in MSNs, but their respective roles in dopamine signal integration remain poorly understood. EXPERIMENTAL APPROACH: We used genetically-encoded FRET biosensors to monitor at the single cell level the functional contribution of PDE2A, PDE4 and PDE10A in the changes of the cAMP/PKA response to transient and continuous dopamine in mouse striatal brain slices...

Camk2a-Cre mice have been widely used to study the postnatal function of several genes in forebrain projection neurons, including cortical projection neurons (CPNs) and striatal medium-sized spiny neurons (MSNs). We linked heterozygous deletion of TSHZ3/Tshz3 gene to autism spectrum disorder (ASD) and used Camk2a-Cre mice to investigate the postnatal function of Tshz3 , which is expressed by CPNs but not MSNs. Recently, single-cell transcriptomics of the adult mouse striatum revealed the expression of Camk2a in interneurons and showed Tshz3 expression in striatal cholinergic interneurons (SCINs), which are attracting increasing interest in the field of ASD...

Intracellular signaling with cyclic nucleotides are ubiquitous signaling pathways, yet the dynamics of these signals profoundly differ in different cell types. Biosensor imaging experiments, by providing direct measurements in intact cellular environment, reveal which receptors are activated by neuromodulators and how the coincidence of different neuromodulators is integrated at various levels in the signaling cascade. Phosphodiesterases appear as one important determinant of cross-talk between different signaling pathways...

Exposure to adversity during early childhood and adolescence increases an individual's vulnerability to developing substance use disorder. Despite the knowledge of this vulnerability, the mechanisms underlying it are still poorly understood. Excitatory afferents to the nucleus accumbens (NAc) mediate responses to both stressful and rewarding stimuli. Understanding how adolescent social isolation alters these afferents could inform the development of targeted interventions both before and after drug use. Here, we used social isolation rearing as a model of early life adversity which we have previously demonstrated increases vulnerability to cocaine addiction-like behaviour...