Reduced expression of conditioned fear in the R6/2 mouse model of Huntington's disease is related to abnormal activity in prelimbic cortex

Walker, Adam G.; Ummel, J; Rebec, George V.

doi:10.1016/j.nbd.2011.04.009

Cited by 19 publications

(15 citation statements)

References 51 publications

(74 reference statements)

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“…Moreover, PL neurons provide reinforcing feedback by sending robust projections to the amygdala, which may help drive freezing behavior. Furthermore, as the animals successfully extinguish fear responding, CS-induced firing of mPFC/PL neurons diminishes (38)(39)(40). Our data raise the intriguing possibility that this lasting depression of CS-induced firing in this mPFC subregion is an mGlu 3 -dependent process and could reflect a lasting depression of transmission from amygdala afferents.…”

Section: Discussionmentioning

confidence: 63%

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Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Walker¹,

Wenthur²,

Xiang³

et al. 2015

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

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Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu 3 ) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu 3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu 3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu 3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu 3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu 3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.etabotropic glutamate receptor 3 (mGlu 3 ) has become of increasing clinical interest due to its genetic association with psychiatric conditions. For example, several studies have identified single-nucleotide polymorphisms (SNPs) in GRM3, the human gene encoding mGlu 3 , that are associated with poor performance on cognitive tests that are dependent on function of the prefrontal cortex (PFC) and hippocampus (1, 2). Additionally, these SNPs have also been associated with variations in functional magnetic resonance imaging (fMRI) indexes of prefrontal cortical activity during working memory tasks (1, 3). Moreover, converging lines of evidence indicate that GRM3 represents a major locus associated with schizophrenia (1, 2, 4), bipolar disorder (5, 6), and substance abuse disorders (6-8). Because mGlu 3 is densely expressed in PFC (9), a brain region implicated as a site of pathology in these disorders (10-12), this genetic evidence has led to an increased interest in determining the role of mGlu 3 in regulating PFC function and behavior.Previous studies have revealed that pharmacological activation of group II mGlu receptors (mGlu 2 and mGlu 3 ) results in longterm depression (LTD) of excitatory transmission in layer V of the rat medial prefrontal cortex (mPFC) (13-16). Although it is not known whether induction of LTD in the mPFC is mediated by mGlu 2 or mGlu 3 , previous studies suggest that presynaptically localized mGlu 2 is typically responsible for inhibition of synaptic transmission by group II mGlu receptor agonists at other synapses (17-23). However, evidence suggests that induction of LTD in the mPFC is dependent upon activation of a postsynaptic group II mGlu receptor (15, 16), suggesting that this response is mechanistically distinct from presynaptic effects of group II mGlu receptor agonists on transmission at other synapses. Unfortunately, a lack of pharmacological agents that can selectively antagonize mGlu 3 or mGlu 2 has impaired progress in this area. To allow us to begin studies aimed at understanding the role of mGlu 3 in regulation of mPFC function, we developed a series of negative allosteric modulator...

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Section: Discussionmentioning

confidence: 63%

“…In vivo recordings have demonstrated that activity within the PL cortex, the region of the mPFC where we studied LTD, is correlated with freezing behavior during fear extinction (32,(38)(39)(40). During states of high fear and freezing, neurons within the PL will display robust firing in response to fear cues, such as a tone CS.…”

Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Walker¹,

Wenthur²,

Xiang³

et al. 2015

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

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“…In tgHD rats, both reversal learning and fear conditioning were impaired [272], similar results were found in YAC128 mice [273, 274]. Similarly, R6/2 mice have difficulty extinguishing conditioned fear, an effect that correlated with altered activity in prefrontal cortex [275]. In a two-choice swim test, Q175 mice showed an increased latency in decision making [55].…”

Section: Dopamine Modulationmentioning

confidence: 78%

“…It already is clear from work on the R6/2 mouse model that information processing in the PFC is altered in HD mice [57]. In fact, abnormal neuronal activity in the prelimbic cortex, a region of the PFC with close ties to the amygdala, is correlated with reduced fear conditioning [275]. Although dysregulation of the corticostriatal circuit has been linked to motor and cognitive alterations in HD [36, 85, 86, 275, 311], very few studies have addressed the issue of DA system changes in HD associated with psychiatric disorders.…”

Section: Dopamine Modulationmentioning

confidence: 99%

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Rangel‐Barajas

Rebec

2016

JHD

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Aberrant communication between striatum, the main information processing unit of the basal ganglia, and cerebral cortex plays a critical role in the emergence of Huntington’s disease (HD), a fatal monogenetic condition that typically strikes in the prime of life. Although both striatum and cortex undergo substantial cell loss over the course of HD, corticostriatal circuits become dysfunctional long before neurons die. Understanding the dysfunction is key to developing effective strategies for treating a progressively worsening triad of motor, cognitive, and psychiatric symptoms. Cortical output neurons drive striatal activity through the release of glutamate, an excitatory amino acid. Striatal outputs, in turn, release γ-amino butyric acid (GABA) and exert inhibitory control over downstream basal ganglia targets. Ample evidence from transgenic rodent models points to dysregulation of corticostriatal glutamate transmission along with corresponding changes in striatal GABA release as underlying factors in the HD behavioral phenotype. Another contributor is dysregulation of dopamine (DA), a modulator of both glutamate and GABA transmission. In fact, pharmacological manipulation of DA is the only currently available treatment for HD symptoms. Here, we review data from animal models and human patients to evaluate the role of DA in HD, including DA interactions with glutamate and GABA within the context of dysfunctional corticostriatal circuitry.

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“…The loss of correlated or synchronous firing among groups of cortical neurons across different models is a key point for HD because cooperative interactions among functionally related neurons, which are often manifest as synchronous oscillatory activity, shape behavioral output (9,14,84). In support of this view, dysregulation of prelimbic activity occurs in R6/2 mice during abnormalities in the extinction of fear conditioning (126).…”

Section: Altered Corticostriatal Processingmentioning

confidence: 97%

Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease

Rebec

2013

Antioxidants & Redox Signaling

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Significance: Dysregulation of cortical and striatal neuronal processing plays a critical role in Huntington's disease (HD), a dominantly inherited condition that includes a progressive deterioration of cognitive and motor control. Growing evidence indicates that ascorbate (AA), an antioxidant vitamin, is released into striatal extracellular fluid when glutamate is cleared after its release from cortical afferents. Both AA release and glutamate uptake are impaired in the striatum of transgenic mouse models of HD owing to a downregulation of glutamate transporter 1 (GLT1), the protein primarily found on astrocytes and responsible for removing most extracellular glutamate. Improved understanding of an AA-glutamate interaction could lead to new therapeutic strategies for HD. Recent Advances: Increased expression of GLT1 following treatment with ceftriaxone, a beta-lactam antibiotic, increases striatal glutamate uptake and AA release and also improves the HD behavioral phenotype. In fact, treatment with AA alone restores striatal extracellular AA to wild-type levels in HD mice and not only improves behavior but also improves the firing pattern of neurons in HD striatum. Critical Issues: Although evidence is growing for an AA-glutamate interaction, several key issues require clarification: the site of action of AA on striatal neurons; the precise role of GLT1 in striatal AA release; and the mechanism by which HD interferes with this role. Future Directions: Further assessment of how the HD mutation alters corticostriatal signaling is an important next step. A critical focus is the role of astrocytes, which express GLT1 and may be the primary source of extracellular AA.

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Reduced expression of conditioned fear in the R6/2 mouse model of Huntington's disease is related to abnormal activity in prelimbic cortex

Cited by 19 publications

References 51 publications

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease

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