Mouse Behavioral Assays Relevant to the Symptoms of Autism*

Crawley, Jacqueline N.

doi:10.1111/j.1750-3639.2007.00096.x

Cited by 505 publications

(454 citation statements)

References 208 publications

(317 reference statements)

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“…Isolation-induced ultrasonic vocalizations (USVs) are an infantmother vocal communicative behavior that is thought to be relevant to autism (14,20). We found that Prex1 −/− pups emitted significantly fewer ultrasonic calls than did WT littermates (Fig.…”

Section: Significancementioning

confidence: 78%

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Chai

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs. Several studies have documented impairments of social recognition [e.g., such as deficits in recognizing unfamiliar faces (2)] and in behavioral flexibility [e.g., impaired reversal learning and difficulties in error correction (3, 4)] in autistic people. However, the neurobiological mechanism responsible for the symptoms of ASDs, and especially for the deficit in social recognition, is little known.Recent genetic studies have identified a large number of candidate genes for ASDs (5, 6), including many that code for synaptic proteins. Synaptic dysfunction may play a critical role in ASDs (7).Here we have identified a new autism-associated gene, Prex1, that codes for P-Rex1 (phosphatidylinositol-3,4,5-trisphosphatedependent Rac exchange factor 1), a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF). This gene is known to be highly expressed in neutrophils and in the mouse brain (8). Mice with the Prex1 gene deleted (Prex1 −/− ) exhibited Racdependent mild neutrophilia (9) and melanoblast migration defects (10). P-Rex1 influences neuronal cell motility (11) and neurite elongation (12) by regulating actin dynamics specifically at the growth cone. However, the role of P-Rex1 in regulating synaptic function and related behaviors remains unknown.In addition to identifying an association between PREX1 and autism in humans, we demonstrate that genetic disruption of P-Rex1 in mice leads to autism-like social behavior and to other features known to be associated with ASDs. Electrophysiological studies revealed a specific impairment of NMDA receptor (NMDAR)-dependent long-term depression (LTD) at Schaffer collateralcornus ammonis region 1 (SC-CA1) synapses. Furthermore, these defects were associated with dysfunction in NMDA-induced AMPA receptor (AMPAR) endocytosis, because of defective PP1α (serine/threonine protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling, and correcting the latter rectified the social recognition defici...

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Section: Significancementioning

confidence: 78%

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Chai

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…On the background of this apparent normality, the three major behavioral impairments that we observed are remarkable. (i) We detected a large increase in repetitive grooming behaviors, indicating an abnormality with face validity to one of the three major symptom domains relevant to autism (31,40). (ii) We measured a decrease in PPI, suggesting impaired sensorimotor gating.…”

Section: Discussionmentioning

confidence: 99%

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Etherton¹,

Blaiss²,

Powell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

410

369

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Deletions in the neurexin-1␣ gene were identified in large-scale unbiased screens for copy-number variations in patients with autism or schizophrenia. To explore the underlying biology, we studied the electrophysiological and behavioral phenotype of mice lacking neurexin-1␣. Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1␣ deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. This defect was specific for excitatory synaptic transmission, because no change in inhibitory synaptic transmission was observed in the hippocampus. Behavioral studies revealed that, compared with littermate control mice, neurexin-1␣ deficient mice displayed a decrease in prepulse inhibition, an increase in grooming behaviors, an impairment in nestbuilding activity, and an improvement in motor learning. However, neurexin-1␣ deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning. Together, these data indicate that the neurexin-1␣ deficiency induces a discrete neural phenotype whose extent correlates, at least in part, with impairments observed in human patients.autism ͉ neuroligin ͉ schizophrenia ͉ synaptic cell-adhesion ͉ synapse N eurexins are neuronal cell-surface proteins that were identified as receptors for ␣-latrotoxin, a presynaptic toxin that triggers massive neurotransmitter release (1-3). Neurexins are largely presynaptic proteins that form a transsynaptic celladhesion complex with postsynaptic neuroligins (4, 5). Vertebrates express three neurexin genes, each of which includes two promoters that direct the synthesis of the longer ␣-neurexins and the shorter ␤-neurexins (6, 7). Neurexins are expressed in all neurons, and are subject to extensive alternative splicing, generating Ͼ1,000 splice variants, some of which exhibit highly regulated developmental and spatial expression patterns (8).The properties of neurexins suggested that they function as synaptic recognition molecules (1), and mediate transsynaptic interactions via binding to neuroligins (4). In support of this overall concept, ␣-neurexin triple KO mice exhibit major impairments in synaptic transmission that manifest largely, but not exclusively, as presynaptic changes (9-13). Importantly, ␣-neurexin KO mice do not display a major decrease in the number of excitatory synapses, and only a moderate decrease in inhibitory synapses (9, 13). Thus, neurexins appear to be essential components of synaptic function whose roles extend to several different components of synapses.In recent years, enormous progress in human genetics has led to the identification of multiple genes that are linked to autism spectrum disorders (ASDs) and schizophrenia. Interestingly, copy-number variations in the neurexin-1␣ gene (but not the neurexin-1␤ gene) were repeatedly observed in patients with ASDs (14 -21) and schizophrenia (22-25). Because 0.5% of all ASD cases appear to harbor neurexin-1␣ gen...

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“…Isolation-induced USVs are inherently social (Hofer et al, 2002;Harmon et al, 2008), and reductions of USVs have been found in rodent models of ASDs (Crawley, 2007;Higashida et al, 2011). Diminished USVs in rat pups are suggested to model the lack of crying observed in some children with ASDs (Crawley, 2007). The early deficit in USV production may therefore reflect social dysfunction that persists into adulthood.…”

Section: Discussionmentioning

confidence: 99%

“…The pitch of USVs from control pups decreased with age, as previously reported (Kromkhun et al, 2013), but increased with age in PS pups, further suggesting atypical development following PS. Isolation-induced USVs are inherently social (Hofer et al, 2002;Harmon et al, 2008), and reductions of USVs have been found in rodent models of ASDs (Crawley, 2007;Higashida et al, 2011). Diminished USVs in rat pups are suggested to model the lack of crying observed in some children with ASDs (Crawley, 2007).…”

Section: Discussionmentioning

confidence: 99%

Prenatal Stress Alters the Development of Socioemotional Behavior and Amygdala Neuron Excitability in Rats

Ehrlich

Rainnie

2015

Neuropsychopharmacol

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Prenatal stress (PS) is a risk factor for neurodevelopmental disorders with diverse ages of onset and socioemotional symptoms. Some PS-linked disorders involve characteristic social deficits, such as autism spectrum disorders and schizophrenia, but PS also promotes anxiety disorders. We propose the diversity of symptoms following PS arises from perturbations to early brain development. To this end, we characterized the effects of PS on the developmental trajectory of physiology of the amygdala, a late-developing center for socioemotional control. We found that PS dampened socioemotional behavior and reduced amygdala neuron excitability in offspring during infancy (at postnatal days (P)10, 14, 17 and 21), preadolescence (day 28), and adulthood (day 60). PS offspring in infancy produced fewer isolation-induced vocalizations and in adulthood exhibited less anxiety-like behavior and deficits in social interaction. PS neurons had a more hyperpolarized resting membrane potential from infancy to adulthood and produced fewer action potentials. Moreover, adult amygdala neurons from PS animals expressed larger action potential afterhyperpolarizations and H-current relative to controls, further limiting excitability. Our results suggest that PS can suppress socioemotional behavior throughout development and produce age-specific alterations to amygdala physiology.

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Mouse Behavioral Assays Relevant to the Symptoms of Autism*

Cited by 505 publications

References 208 publications

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Prenatal Stress Alters the Development of Socioemotional Behavior and Amygdala Neuron Excitability in Rats

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