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David M Lovinger - One of the best experts on this subject based on the ideXlab platform.

  • Age-dependent impairment of metabotropic glutamate receptor 2-dependent long-term depression in the mouse Striatum by chronic ethanol exposure.
    Alcohol (Fayetteville N.Y.), 2019
    Co-Authors: Kari A Johnson, Daniel J. Liput, Gregg E. Homanics, David M Lovinger
    Abstract:

    Abstract Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the Dorsolateral Striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu2) is a Gi/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu2 function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu2 function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the Striatum to assess CIE effects on mGlu2-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu2-mediated long-term depression in the DLS vs. dorsomedial Striatum (DMS). Interestingly, CIE-induced impairment of mGlu2-LTD in the Dorsolateral Striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu2 fully rescues mGlu2-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu2-LTD. We did not observe a reduction of mGlu2 mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu2 occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu2 activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

  • active zone proteins rim1αβ are required for normal corticostriatal transmission and action control
    The Journal of Neuroscience, 2019
    Co-Authors: David A Kupferschmidt, Kari A Johnson, Shana M Augustin, David M Lovinger
    Abstract:

    Dynamic regulation of synaptic transmission at cortical inputs to the dorsal Striatum is considered critical for flexible and efficient action learning and control. Presynaptic mechanisms governing the properties and plasticity of glutamate release from these inputs are not fully understood, and the corticostriatal synaptic processes that support normal action learning and control remain unclear. Here we show in male and female mice that conditional deletion of presynaptic proteins RIM1αβ (RIM1) from excitatory cortical neurons impairs corticostriatal synaptic transmission in the Dorsolateral Striatum. Key forms of presynaptic G-protein-coupled receptor-mediated short- and long-term striatal plasticity are spared following RIM1 deletion. Conditional RIM1 KO mice show heightened novelty-induced locomotion and impaired motor learning on the accelerating rotarod. They further show heightened self-paced instrumental responding for food and impaired learning of a habitual instrumental response strategy. Together, these findings reveal a selective role for presynaptic RIM1 in neurotransmitter release at prominent basal ganglia synapses, and provide evidence that RIM1-dependent processes help to promote the refinement of skilled actions, constrain goal-directed behaviors, and support the learning and use of habits.SIGNIFICANCE STATEMENT Our daily functioning hinges on the ability to flexibly and efficiently learn and control our actions. How the brain encodes these capacities is unclear. Here we identified a selective role for presynaptic proteins RIM1αβ in controlling glutamate release from cortical inputs to the Dorsolateral Striatum, a brain structure critical for action learning and control. Behavioral analysis of mice with restricted genetic deletion of RIM1αβ further revealed roles for RIM1αβ-dependent processes in the learning and refinement of motor skills and the balanced expression of goal-directed and habitual actions.

  • Gradient of CB1-R expression in the Dorsolateral Striatum.
    2018
    Co-Authors: Margaret I. Davis, David A Kupferschmidt, Jill R. Crittenden, Austin Y. Feng, Alipi Naydenov, Nephi Stella, Ann M. Graybiel, David M Lovinger
    Abstract:

    (A) A representative section immunostained for CB1-R with the angle and regions quantified. (B) A representative histogram of the mean intensity of a strip taken from this angle at a width of 500 pixels (1.028 pixels/ μm). (C) The optical density of the regions sampled along the Dorsolateral-to-ventromedial gradient from nine individual slices from 6 mice sampled in the peri-commissural and post-commissural Striatum are plotted as individual points. CB1-R expression gradient (D, D”) compared to D1-tdTomato expression gradient (D, D’). A representative histogram for D1-tdTomato levels is shown in E. Arrows in D and E indicate the change in the D1-tdTomato gradient. *p

  • inhibition of presynaptic calcium transients in cortical inputs to the Dorsolateral Striatum by metabotropic gabab and mglu2 3 receptors
    The Journal of Physiology, 2015
    Co-Authors: David A Kupferschmidt, David M Lovinger
    Abstract:

    Key points Plastic changes at cortical inputs to the Dorsolateral Striatum (DLS) underlie skill learning and habit formation, so characterizing the mechanisms by which these inputs are regulated is important for understanding the neural basis of action control. We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 and brain slice photometry to assess evoked presynaptic Ca2+ transients in cortical inputs to the DLS and study their regulation by GABAB and mGlu2/3 receptors. GABAB and mGlu2/3 receptor activation caused clear reductions in electrical stimulus-evoked presynaptic Ca2+ transients in corticostriatal inputs to the DLS. Functional P/Q-type voltage-gated Ca2+ channels were required for the normal inhibitory action of corticostriatal mGlu2/3 receptors. We provide direct evidence of presynaptic Ca2+ inhibition by G protein-coupled receptors at corticostriatal projections. Abstract Cortical inputs to the Dorsolateral Striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS-associated circuit function, behaviour and pathology. Presynaptic GABAB and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 to assess presynaptic Ca2+ in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca2+ and striatal field potential recordings, we report that relative to P/Q-type Ca2+ channels, N-type channels preferentially contributed to evoked presynaptic Ca2+ influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABAB or mGlu2/3 receptors inhibited both evoked presynaptic Ca2+ transients and striatal field potentials. mGlu2/3 receptor-mediated depression did not require functional N-type Ca2+ channels, but was attenuated by blockade of P/Q-type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires.

  • optogenetic measurement of presynaptic calcium transients using conditional genetically encoded calcium indicator expression in dopaminergic neurons
    PLOS ONE, 2014
    Co-Authors: Carmelo Sgobio, David A Kupferschmidt, Guohong Cui, Lixin Sun, Huaibin Cai, David M Lovinger
    Abstract:

    Calcium triggers dopamine release from presynaptic terminals of midbrain dopaminergic (mDA) neurons in the Striatum. However, calcium transients within mDA axons and axon terminals are difficult to study and little is known about how they are regulated. Here we use a newly-developed method to measure presynaptic calcium transients (PreCaTs) in axons and terminals of mDA neurons with a genetically encoded calcium indicator (GECI) GCaMP3 expressed in transgenic mice. Using a photomultiplier tube-based system, we measured electrical stimulation-induced PreCaTs of mDA neurons in Dorsolateral Striatum slices from these mice. Single-pulse stimulation produced a transient increase in fluorescence that was completely blocked by a combination of N- and P/Q-type calcium channel blockers. DA and cholinergic, but not serotoninergic, signaling pathways modulated the PreCaTs in mDA fibers. These findings reveal heretofore unexplored dynamic modulation of presynaptic calcium in nigrostriatal terminals.

Jill B Becker - One of the best experts on this subject based on the ideXlab platform.

  • g protein coupled estradiol receptor 1 in Dorsolateral Striatum modulates cocaine preference in male rats
    bioRxiv, 2019
    Co-Authors: J A Quigley, Jill B Becker
    Abstract:

    Abstract There are sex differences in susceptibility to addiction. Cultural influences play a role in drug seeking behaviors; however, sex differences are found in rodent models of addiction as well, suggesting that there are also neurobiological factors involved. Extensive research has shown that estradiol facilitates enhanced motivation and drug seeking in female but not male rodents. Estradiol treatment also potentiates cocaine induced dopamine overflow in the Dorsolateral Striatum (DLS) of females. Together, these findings suggest that estradiol potentiates the rewarding effects of cocaine in females only. However, testosterone is aromatized to estradiol in the male brain but thus far, it’s action in males is not well understood. These studies used pharmacological treatments to manipulate ERα, ERβ and GPER1 in the DLS to investigate how estradiol receptors regulate preference for cocaine in both sexes. Antagonism of ERα or ERβ did not alter cocaine CPP in males, but GPER1 activation blocked cocaine preference and inhibition of GPER1 enhanced cocaine CPP in males. Surprisingly, there was no effect of GPER1 activation in females. There were no sex differences in relative mRNA expression of ERα, ERβ and GPER1 in the dorsal Striatum. Together, these results indicate that estradiol is playing differential roles in males and females such that it may be protective against drug seeking in male rats while enhancing it in females. Significance Statement Drug addiction effects men and women differently but the way we treat addiction is not tailored by sex like it should be. Apart from cultural influence, one reason for sex differences in drug taking could be due to differences in neurobiological function and actions of gonadal hormones. This research article identifies a novel, protective, role for estradiol receptor, GPER1, in male rats only. This discovery could lead to sex-specific therapeutic targets for addiction treatment.

  • Activation of G-protein coupled estradiol receptor 1 in the Dorsolateral Striatum attenuates preference for cocaine and saccharin in male but not female rats
    Cold Spring Harbor Laboratory, 2019
    Co-Authors: J A Quigley, Jill B Becker
    Abstract:

    AbstractThere are sex differences in the response to psychomotor stimulants, where females exhibit a greater response than males, due to the presence of the gonadal hormone estradiol (E2). Extensive research has shown that E2 enhances drug-seeking and the rewarding properties of cocaine for females. The role of E2 in male drug-seeking, however, is not well understood. The current study investigated pharmacological manipulation of E2 receptors in the Dorsolateral Striatum (DLS) on preference for cocaine in gonad-intact male and female rats. In males, activation of G-protein coupled E2 receptor 1 (GPER1), via administration of ICI 182,780 or G1, attenuated conditioned place preference for 10mg/kg cocaine, while inhibition of GPER1, via G15, enhanced preference at a 5mg/kg cocaine dose. Similarly, GPER1 activation, via G1, prevented males from forming a preference for 0.1% saccharin (SACC) versus plain water. Surprisingly, activation of GPER1 did not alter preference for cocaine or SACC in females. These studies also examined the quantity of E2 receptor mRNA in the dorsal Striatum, using qPCR. No sex differences in relative mRNA expression of ERα, ERβ, and GPER1 were observed. However, there was greater GPER1 mRNA, relative to ERα and ERβ, in both males and females. The results presented here indicate that E2, acting via GPER1, may be protective against drug preference in male rats.

  • sex differences in addiction
    Dialogues in clinical neuroscience, 2016
    Co-Authors: Jill B Becker
    Abstract:

    Women exhibit more rapid escalation from casual drug taking to addiction, exhibit a greater withdrawal response with abstinence, and tend to exhibit greater vulnerability than men in terms of treatment outcome. In rodents, short-term estradiol intake in female rats enhances acquisition and escalation of drug taking, motivation for drugs of abuse, and relapse-like behaviors. There is also a sex difference in the dopamine response in the nucleus accumbens. Ovariectomized female rats exhibit a smaller initial dopamine increase after cocaine treatment than castrated males. Estradiol treatment of ovariectomized female rats enhances stimulated dopamine release in the Dorsolateral Striatum, but not in the nucleus accumbens, resulting in a sex difference in the balance between these two dopaminergic projections. In the situation where drug-taking behavior becomes habitual, dopamine release has been reported to be enhanced in the Dorsolateral Striatum and attenuated in the nucleus accumbens. The sex difference in the balance between these neural systems is proposed to underlie sex differences in addiction.

Mark G. Packard - One of the best experts on this subject based on the ideXlab platform.

  • post training re exposure to fear conditioned stimuli enhances memory consolidation and biases rats toward the use of Dorsolateral Striatum dependent response learning
    Behavioural Brain Research, 2015
    Co-Authors: Kahchung Leong, Jarid Goodman, Mark G. Packard
    Abstract:

    Abstract In a dual-solution task that can be acquired using either hippocampus-dependent “place” or Dorsolateral Striatum-dependent “response” learning, emotional arousal induced by unconditioned stimuli (e.g. anxiogenic drug injections or predator odor exposure) biases rats toward response learning. In the present experiments emotionally-arousing conditioned stimuli were used to modulate the relative use of multiple memory systems. In Experiment 1, adult male Long-Evans rats initially received three standard fear-conditioning trials in which a tone (2 kHz, 75 dB) was paired with a brief electrical shock (1 mA, 2 s). On day 2, the rats were trained in a dual-solution plus-maze task to swim from the same start arm (South) to a hidden escape platform always located in the same goal arm (East). Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli (i.e. tone and context) without shock. On day 3, the relative use of place or response learning was assessed on a probe trial in which rats were started from the opposite start arm (North). Post-training re-exposure to fear-conditioned stimuli produced preferential use of a response strategy. In Experiment 2, different rats received fear conditioning and were then trained in a single-solution task that required the use of response learning. Immediately following training, rats received post-training re-exposure to the fear-conditioned stimuli without shock. Re-exposure to fear-conditioned stimuli enhanced memory consolidation in the response learning task. Thus, re-exposure to fear- conditioned stimuli biases rats toward the use of Dorsolateral Striatum-dependent response learning and enhances memory consolidation of response learning.

  • Differential effects of massed and spaced training on place and response learning: A memory systems perspective.
    Behavioural processes, 2015
    Co-Authors: Jeffrey C. Wingard, Jarid Goodman, Kahchung Leong, Mark G. Packard
    Abstract:

    Studies employing brain lesion or intracerebral drug infusions in rats have demonstrated a double dissociation between the roles of the hippocampus and Dorsolateral Striatum in place and response learning. The hippocampus mediates a rapid cognitive learning process underlying place learning, whereas the Dorsolateral Striatum mediates a relatively slower learning process in which stimulus-response habits underlying response learning are acquired in an incremental fashion. One potential implication of these findings is that hippocampus-dependent learning may benefit from a relative massing of training trials, whereas dorsal Striatum-dependent learning may benefit from a relative distribution of training trials. In order to examine this hypothesis, the present study compared the effects of massed (30s inter-trial interval; ITI) or spaced (30min ITI) training on acquisition of a hippocampus-dependent place learning task, and a Dorsolateral Striatum-dependent response task in a plus-maze. In the place task rats swam from varying start points (N or S) to a hidden escape platform located in a consistent spatial location (W). In the response task rats swam from varying start points (N or S) to a hidden escape platform located in the maze arm consistent with a body-turn response (left). In the place task, rats trained with the massed trial schedule acquired the task quicker than rats trained with the spaced trial schedule. In the response task, rats trained with the spaced trial schedule acquired the task quicker than rats trained with the massed trial schedule. The double dissociation observed suggests that the reinforcement parameters most conducive to effective learning in hippocampus-dependent and Dorsolateral Striatum-dependent learning may have differential temporal characteristics.

  • Peripheral and intra-Dorsolateral Striatum injections of the cannabinoid receptor agonist WIN 55,212-2 impair consolidation of stimulus–response memory
    Neuroscience, 2014
    Co-Authors: Jarid Goodman, Mark G. Packard
    Abstract:

    Abstract The endocannabinoid system plays a major role in modulating memory. In the present study, we examined whether cannabinoid agonists influence the consolidation of stimulus–response/habit memory, a form of memory dependent upon the Dorsolateral Striatum (DLS). In Experiment 1, rats were trained in a cued platform water maze task in which animals were released from different start points and in order to escape had to find a cued platform which was moved to various spatial locations across trials. Immediately following training, rats received an i.p. injection of the cannabinoid receptor agonist WIN 55,212-2 (1 or 3 mg/kg) or a vehicle solution. In Experiment 2, rats were trained in a forced-response version of the water plus-maze task in which a consistent body-turn response was reinforced across trials. Immediately following training, rats received an i.p. injection of WIN 55,212-2 (3 mg/kg) or vehicle. In Experiment 3, rats were trained in the cued platform task and after training received bilateral intra-DLS WIN 55,212-2 (100 ng/.5 μL or 200 ng/.5 μL) or vehicle. In Experiments 1–3, the higher doses of WIN 55,212-2 were associated with significant memory impairments, relative to vehicle-treated controls. The results indicate that peripheral or intra-DLS administration of a cannabinoid receptor agonist impairs consolidation of DLS-dependent memory. The findings are discussed within the context of previous research encompassing cannabinoids and DLS-dependent learning and memory processes, and the possibility that cannabinoids may be used to treat some habit-like human psychopathologies (e.g. posttraumatic stress disorder) is considered.

Min Whan Jung - One of the best experts on this subject based on the ideXlab platform.

  • Neuronal activity in dorsomedial and Dorsolateral Striatum under the requirement for temporal credit assignment
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Eun Sil Her, Namjung Huh, Jieun Kim, Min Whan Jung
    Abstract:

    To investigate neural processes underlying temporal credit assignment in the Striatum, we recorded neuronal activity in the dorsomedial and Dorsolateral Striatum (DMS and DLS, respectively) of rats performing a dynamic foraging task in which a choice has to be remembered until its outcome is revealed for correct credit assignment. Choice signals appeared sequentially, initially in the DMS and then in the DLS, and they were combined with action value and reward signals in the DLS when choice outcome was revealed. Unlike in conventional dynamic foraging tasks, neural signals for chosen value were elevated in neither brain structure. These results suggest that dynamics of striatal neural signals related to evaluating choice outcome might differ drastically depending on the requirement for temporal credit assignment. In a behavioral context requiring temporal credit assignment, the DLS, but not the DMS, might be in charge of updating the value of chosen action by integrating choice, action value, and reward signals together1331Nsciescopu

  • neuronal activity in dorsomedial and Dorsolateral Striatum under the requirement for temporal credit assignment
    Scientific Reports, 2016
    Co-Authors: Eun Sil Her, Namjung Huh, Jieun Kim, Min Whan Jung
    Abstract:

    To investigate neural processes underlying temporal credit assignment in the Striatum, we recorded neuronal activity in the dorsomedial and Dorsolateral Striatum (DMS and DLS, respectively) of rats performing a dynamic foraging task in which a choice has to be remembered until its outcome is revealed for correct credit assignment. Choice signals appeared sequentially, initially in the DMS and then in the DLS, and they were combined with action value and reward signals in the DLS when choice outcome was revealed. Unlike in conventional dynamic foraging tasks, neural signals for chosen value were elevated in neither brain structure. These results suggest that dynamics of striatal neural signals related to evaluating choice outcome might differ drastically depending on the requirement for temporal credit assignment. In a behavioral context requiring temporal credit assignment, the DLS, but not the DMS, might be in charge of updating the value of chosen action by integrating choice, action value, and reward signals together.

  • signals for previous goal choice persist in the dorsomedial but not Dorsolateral Striatum of rats
    The Journal of Neuroscience, 2013
    Co-Authors: Hoseok Kim, Daeyeol Lee, Min Whan Jung
    Abstract:

    The cortico-basal ganglia network has been proposed to consist of parallel loops serving distinct functions. However, it is still uncertain how the content of processed information varies across different loops and how it is related to the functions of each loop. We investigated this issue by comparing neuronal activity in the Dorsolateral (sensorimotor) and dorsomedial (associative) Striatum, which have been linked to habitual and goal-directed action selection, respectively, in rats performing a dynamic foraging task. Both regions conveyed significant neural signals for the animal's goal choice and its outcome. Moreover, both regions conveyed similar levels of neural signals for action value before the animal's goal choice and chosen value after the outcome of the animal's choice was revealed. However, a striking difference was found in the persistence of neural signals for the animal's chosen action. Signals for the animal's goal choice persisted in the dorsomedial Striatum until the outcome of the animal's next goal choice was revealed, whereas they dissipated rapidly in the Dorsolateral Striatum. These persistent choice signals might be used for causally linking temporally discontiguous responses and their outcomes in the dorsomedial Striatum, thereby contributing to its role in goal-directed action selection.

Soo Young Kim - One of the best experts on this subject based on the ideXlab platform.

  • Taesun Yoo,1 Sun-Gyun Kim,2 Soo Hyun Yang,3 Hyun Kim,3 Eunjoon Kim,1,2 and Soo Young Kimcorresponding author4
    BMC, 2020
    Co-Authors: Taesun Yoo, Sun-gyun Kim, Soo Hyun Yang, Hyun Kim, Eunjoon Kim, Soo Young Kim
    Abstract:

    Background DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. Methods Mice lacking exon 14 of the Dlg2 gene (Dlg2(-/-) mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the Dorsolateral Striatum. Results Dlg2(-/-) mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2(-/-) mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the Striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2(-/-) Dorsolateral Striatum was significantly reduced. Conclusion These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto Dorsolateral spiny projection neurons, implying that the dorsal Striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2. C. The Author(s) 202

  • Taesun Yoo,1 Sun-Gyun Kim,2 Soo Hyun Yang,3 Hyun Kim,3 Eunjoon Kim,1,2 and Soo Young Kimcorresponding author4
    'Springer Science and Business Media LLC', 2020
    Co-Authors: Taesun Yoo, Sun-gyun Kim, Soo Hyun Yang, Hyun Kim, Eunjoon Kim, Soo Young Kim
    Abstract:

    Background DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. Methods Mice lacking exon 14 of the Dlg2 gene (Dlg2(-/-) mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the Dorsolateral Striatum. Results Dlg2(-/-) mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2(-/-) mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the Striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2(-/-) Dorsolateral Striatum was significantly reduced. Conclusion These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto Dorsolateral spiny projection neurons, implying that the dorsal Striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2. C. The Author(s) 202011Nsciescopu