Neural Mechanisms Underlying Repetitive Behaviors in Rodent Models of Autism Spectrum Disorders

Abstract

Autism spectrum disorder (ASD) is comprised of several conditions characterized by alterations in social interaction, communication, and repetitive behaviors. Genetic and environmental factors contribute to the heterogeneous development of ASD behaviors. Several rodent models display ASD-like phenotypes, including repetitive behaviors. In this review article, we discuss the potential neural mechanisms involved in repetitive behaviors in rodent models of ASD and related neuropsychiatric disorders. We review signaling pathways, neural circuits, and anatomical alterations in rodent models that display robust stereotypic behaviors. Understanding the mechanisms and circuit alterations underlying repetitive behaviors in rodent models of ASD will inform translational research and provide useful insight into therapeutic strategies for the treatment of repetitive behaviors in ASD and other neuropsychiatric disorders.

Keywords: autism models; circuitry; neural mechanisms; neuroanatomical alterations; repetitive behavior; signaling.

Figure 1

Implicated brain regions in mouse models of autism. Different mouse models of autism exhibit alterations in various brain areas such as the striatum, cortex, thalamus, hippocampus, cerebellum, hypothalamus, and amygdala. These brain regions are involved in cortico-striatal and limbic circuitry. Molecular and/or neuroanatomical changes in these structures are correlated with the pathophysiology of repetitive behaviors. Some mice models implicate multiple brain regions in the pathology of restricted/repetitive behaviors. PFC, prefrontal cortex; VTA, ventral tegmental area; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; PVH, paraventricular nucleus of hypothalamus; Cntnap2, Contactin Associated Protein-like 2 gene; FMR1, Fragile X mental retardation 1; Gabrb3, Gamma-aminobutyric acid receptor subunit beta-3; Hoxb8, Homeobox protein; Itgb3, Integrin beta-3; KCNQ, Potassium voltage-gated channel subfamily; Kirrel3, Kin of Irregular Chiasm-like 3; Lrrc4, Leucine-rich repeat-containing 4; MeCP2, Methyl CpG binding protein 2; Ninj1, Nerve injury-induced protein-1; NL, Neuroligin; NRXN1a, Neurexin 1a; Oxtr, Oxytocin receptor; Pcdh19, Protocadherin-19; PV, Parvalbumin; Pak2, p21 activated kinase 2; Pten, Phosphatase and tensin homolog; Sapap3, Synapse-associated protein 90/postsynaptic density protein 95 associated protein 3; Shank, SH3 and multiple ankyrin repeat domains 3; Sh3rf2, SH3 Domain Containing Ring Finger 2; Scn1, Sodium Voltage-Gated Channel Alpha Subunit 1; Tsc2, Tuberous Sclerosis Complex 2; Ube3A, Ubiquitin Protein Ligase E3A; VPA, Valproic acid; 5Ko, 5 kainate receptor subunit.

Figure 2

Neural mechanisms underlying repetitive behaviors. Increased mGluR5 signaling activates the striatal direct pathway leading to heightened motor cortex activity inducing repetitive behaviors. Impaired NMDA and AMPA receptors in the striatum and hippocampus also mediates stereotypic behaviors. Cortico-striatal and PFC-VTA glutamatergic projections induce repetitive behavior. PFC projections to the SNc causes striatal dopaminergic release promoting movement. The decrease in interneuron activity in the cortex and increase in dopamine D2, D1 receptor expression in the striatum leads to reduced GABAergic signaling in the cortex, enhancing motor cortical activity, and repetitive behaviors. Elevation of serotonin 5HT_2A receptor signaling in the dorsomedial striatum gives rise to stereotypic behaviors. Activation of VGLUT-positive glutamatergic neurons in the amygdala nucleus, MeA also results in stereotypic behaviors. Activation of glutamatergic projection from BLA to the ventral hippocampus leads to an increase in locomotor activity. Further, activation of lateral hypothalamic GABAergic neurons mediates an increase in locomotor activity and repetitive behaviors. Reduction in endocannabinoid 2-AG signaling in the striatum leads to an increase in glutamatergic output, enhancing motor cortex activity resulting in repetitive behaviors. Low astrocytic Ca²⁺ signals in the striatum elevate membrane GAT-3 expression that modulates striatal MSN activity via reduced ambient GABA levels inducing repetitive behavior. mGluR5, metabotropic glutamate receptor 5; NMDA, N-Methyl-d-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; PFC, prefrontal cortex; VTA, ventral tegmental area; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; PVH, paraventricular nucleus of the hypothalamus; GABA, gamma-aminobutyric acid; D2R, dopamine receptor D2; D1R, dopamine receptor D1; 5HT_2A, 5-hydroxy-tryptamine receptor 2A subtype; VGAT, vesicular GABA transporter; MeA, medial nucleus of the amygdala; BLA, basolateral amygdala; 2-AG, 2-arachidonoyl glycerol; GAT-3, GABA transporter 3; MSN, and medium spiny neuron.

Figure 3

Possible mechanisms alleviating repetitive behaviors. Inhibition of mGluR5 signaling inhibits striatal direct pathway via suppressing dopamine D1 receptor signaling. The reduced D1R signaling results in decreased motor cortex activity. Inhibition of cortico-striatal and PFC-VTA glutamatergic projections alleviate repetitive behaviors. Application of GABA agonists in the cortex and dopamine D2R, D1R antagonist in the striatum leads to an increase in GABAergic signaling in the cortex, reducing motor cortical activity and repetitive behaviors. Application of serotonin 5HT_2A antagonist in the dorsomedial striatum also results in the rescue of repetitive behavior. Activation of VGAT-positive GABAergic neurons in the amygdala nucleus, MeA reduces repetitive behaviors. Inhibition of glutamatergic projection from BLA to the ventral hippocampus results in decreased locomotor activity. Inhibition of lateral hypothalamic GABAergic neurons leads to a decrease in locomotor activity and repetitive behaviors. Endocannabinoid 2-AG signaling in the striatum leads to reduced glutamatergic output, decreasing repetitive behaviors. Regulated astrocytes Ca²⁺ signals in the striatum modulate GAT-3 activity which maintains synaptic GABA levels, regulating striatal MSN activity and associated repetitive behavior. mGluR5, metabotropic glutamate receptor 5; NMDA, N-Methyl-d-aspartate; AMPA, α-amino-3-hydroxy -5-methyl-4-isoxazolepropionic acid; PFC, prefrontal cortex; VTA, ventral tegmental area; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; PVH, paraventricular nucleus of the hypothalamus; GABA, gamma-aminobutyric acid; D2R, dopamine receptor D2; D1R, dopamine receptor D1; 5HT_2A, 5-hydroxy-tryptamine receptor 2A subtype; VGAT, vesicular GABA transporter; MeA, medial nucleus of the amygdala; BLA, basolateral amygdala; 2-AG, 2-arachidonoyl glycerol; GAT-3, GABA transporter 3; MSN, the medium spiny neuron.

Figure 4

Endocannabinoid signaling in striatal neurons. DGLα synthesizes 2-AG in the postsynaptic neuron. Postsynaptic 2-AG activates presynaptic cannabinoid-1 receptor (CB1R). The activated CB1 receptor via feedback inhibition leads to suppression of glutamate release at MSN synapses, thereby relieving repetitive behavior. However, mice with knockout of DGLα exhibit decreased striatal 2-AG levels, resulting in unrestricted synaptic glutamate release via an absence of feedback inhibition, thereby leading to elevated grooming behavior in mice. Impaired endocannabinoid signaling is involved in the alteration of striatal activity, contributing to the development of repetitive behavior. CB1R, cannabinoid type 1 receptor; DGLα, diacylglycerol lipase alpha; 2-AG, 2-arachidonoyl glycerol; dMSN, direct pathway medium spiny neurons.

Figure 5

Astrocytic regulation of synaptic glutamate and GABA levels. Normal astrocytic Ca²⁺ signals modulate GAT-3 levels in the presence of Rab11a GTPase mediating GAT-3 endocytosis. As a result, controlled ambient GABA levels in the synapses regulate striatal MSNs activity, resulting in normal behavior. Reduced striatal astrocyte Ca²⁺ signaling contributes to elevated self-grooming behavior via altered striatal MSN activity. Astrocytes also regulate synaptic glutamate levels via transporters like GLT-1. Elevated glutamate levels in the extracellular space induce over-activation of glutamate receptors resulting in excitotoxicity. Astrocytes protect against this excitotoxicity by clearance of synaptic glutamate via glutamate uptake transporters. In astrocytes, glutamate is converted to glutamine which acts as a precursor for re-synthesis of glutamate in neurons, mediating both uptake and release of glutamate. Astrocytes regulate glutamate and GABA in the synapse, thereby modulating neuronal activity and behavior. GABA, gamma-aminobutyric acid; GAT-3, GABA transporter 3; GLT-1, glutamate transporter 1; Rab, small Rab GTPase.