Altered Neuronal Circuitry

2014 ◽  
Author(s):  
Michael S. Levine ◽  
Elizabeth A. Wang ◽  
Jane Y. Chen ◽  
Carlos Cepeda ◽  
Véronique M. André
Keyword(s):  
Mouse Models ◽  
Pyramidal Neurons ◽  
Therapeutic Interventions ◽  
Disease Stage ◽  
Medium Spiny Neurons ◽  
Behavioral Alterations ◽  
Spiny Neurons ◽  
Cortical Pyramidal Neurons ◽  
Late Stages ◽  
Dopamine Modulation

In mouse models of Huntington’s disease (HD), synaptic alterations in the cerebral cortex and striatum are present before overt behavioral symptoms and cell death. Similarly, in HD patients, it is now widely accepted that early deficits can occur in the absence of neural atrophy or overt motor symptoms. In addition, hyperkinetic movements seen in early stages are followed by hypokinesis in the late stages, indicating that different processes may be affected. In mouse models, such behavioral alterations parallel complex biphasic changes in glutamate-mediated excitatory, γ‎-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission and dopamine modulation in medium spiny neurons of the striatum as well as in cortical pyramidal neurons. The progressive electrophysiologic changes in synaptic communication that occur with disease stage in the cortical and basal ganglia circuits of HD mouse models strongly indicate that therapeutic interventions and strategies in human HD must be targeted to different mechanisms in each stage and to specific subclasses of neurons.

Unique Properties of R-Type Calcium Currents in Neocortical and Neostriatal Neurons

2000 ◽  
Vol 84 (5) ◽  
pp. 2225-2236 ◽  
Author(s):  
Robert C. Foehring ◽  
Paul G. Mermelstein ◽  
Wen-Jie Song ◽  
Sasha Ulrich ◽  
D. James Surmeier
Keyword(s):  
Pyramidal Neurons ◽  
Cell Types ◽  
Calcium Currents ◽  
Medium Spiny Neurons ◽  
Cell Type ◽  
Channel Current ◽  
Spiny Neurons ◽  
Deactivation Kinetics ◽  
Whole Cell Recordings ◽  
Neocortical Pyramidal Neurons

Whole cell recordings from acutely dissociated neocortical pyramidal neurons and striatal medium spiny neurons exhibited a calcium-channel current resistant to known blockers of L-, N-, and P/Q-type Ca2+ channels. These R-type currents were characterized as high-voltage–activated (HVA) by their rapid deactivation kinetics, half-activation and half-inactivation voltages, and sensitivity to depolarized holding potentials. In both cell types, the R-type current activated at potentials relatively negative to other HVA currents in the same cell type and inactivated rapidly compared with the other HVA currents. The main difference between cell types was that R-type currents in neocortical pyramidal neurons inactivated at more negative potentials than R-type currents in medium spiny neurons. Ni2+ sensitivity was not diagnostic for R-type currents in either cell type. Single-cell RT-PCR revealed that both cell types expressed the α1E mRNA, consistent with this subunit being associated with the R-type current.

scholarly journals Altered excitatory and inhibitory inputs to striatal medium-sized spiny neurons and cortical pyramidal neurons in the Q175 mouse model of Huntington's disease

2015 ◽  
Vol 113 (7) ◽  
pp. 2953-2966 ◽  
Author(s):  
Tim Indersmitten ◽  
Conny H. Tran ◽  
Carlos Cepeda ◽  
Michael S. Levine
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Primary Motor Cortex ◽  
Pyramidal Neurons ◽  
Membrane Properties ◽  
Postsynaptic Currents ◽  
Spiny Neurons ◽  
Cortical Pyramidal Neurons ◽  
Intrinsic Membrane Properties

The Q175 knockin mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission, using whole cell patch-clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175+/−) and homozygous (Q175+/+) mice. Input resistance in MSNs from Q175+/+ and Q175+/− mice was significantly increased compared with wild-type (WT) littermates beginning at 2 mo. Furthermore, the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was significantly reduced in MSNs from Q175+/+ and Q175+/− mice compared with WTs beginning at 7 mo. In contrast, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and IPSC-to-EPSC ratios were increased in MSNs from Q175+/+ mice beginning at 2 mo. Morphologically, significant decreases in spine density of MSNs from Q175+/− and Q175+/+ mice occurred at 7 and 12 mo. In CPNs, sIPSC frequencies and IPSC-to-EPSC ratios were significantly increased in Q175+/− mice compared with WTs at 12 mo. There were no changes in intrinsic membrane properties or morphology. In summary, we show a number of alterations in electrophysiological and morphological properties of MSNs in Q175 mice that are similar to other HD mouse models. However, unlike other models, CPN inhibitory activity is increased in Q175+/− mice, indicating reduced cortical excitability.

scholarly journals Dysregulated Information Processing by Medium Spiny Neurons in Striatum of Freely Behaving Mouse Models of Huntington's Disease

2008 ◽  
Vol 100 (4) ◽  
pp. 2205-2216 ◽  
Author(s):  
Benjamin R. Miller ◽  
Adam G. Walker ◽  
Anand S. Shah ◽  
Scott J. Barton ◽  
George V. Rebec
Keyword(s):  
Information Processing ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Population Level ◽  
Medium Spiny Neurons ◽  
Processing Scheme ◽  
Background Strain ◽  
Spiny Neurons ◽  
Freely Behaving

Huntington's disease (HD) is an autosomal dominant condition that compromises behavioral output. Dysfunction of medium spiny neurons (MSNs), which are the sole output system of the striatum, is thought to underlie HD pathophysiology. What is not known is how HD alters MSN information processing during behavior, which likely drives the HD behavioral phenotype. We recorded from populations of MSNs in two freely behaving and symptomatic HD mouse models: R6/2 transgenics are based on a C57BL/6J*CBA/J background and show robust behavioral symptoms, whereas knock-in (KI) mice have a 129sv background and express relatively mild behavioral signs. At the single-unit level, we found that the MSN firing rate was elevated in R6/2 but not in KI mice compared with their respective wild-type (WT) controls. In contrast, burst activity, which corresponds to periods of high-frequency firing, was altered in both HD models compared with WT. At the population level, we found that correlated firing between pairs of MSNs was a prominent feature in WT that was reduced in both HD models. Similarly, coincident bursts, which are bursts between pairs of neurons that overlap in time and occur more often in pairs of MSNs that exhibit correlated firing, were decreased in HD mice. Our results indicate an important role in both bursting and correlated burst firing for information processing in MSNs. Dysregulation of this processing scheme, moreover, is a key component of HD pathophysiology regardless of the severity of HD symptoms, genetic construct, and background strain of the mouse models.

scholarly journals Bidirectional Dopamine Modulation of GABAergic Inhibition in Prefrontal Cortical Pyramidal Neurons

2001 ◽  
Vol 21 (10) ◽  
pp. 3628-3638 ◽  
Author(s):  
Jeremy K. Seamans ◽  
Natalia Gorelova ◽  
Daniel Durstewitz ◽  
Charles R. Yang
Keyword(s):  
Pyramidal Neurons ◽  
Gabaergic Inhibition ◽  
Prefrontal Cortical ◽  
Cortical Pyramidal Neurons ◽  
Dopamine Modulation

scholarly journals Synapse-specific Opioid Modulation of Thalamo-cortico-striatal Circuits

2019 ◽  
Author(s):  
William T. Birdsong ◽  
Bart C. Jongbloets ◽  
Kim A. Engeln ◽  
Dong Wang ◽  
Gregory Scherrer ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pyramidal Neurons ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Delta Opioid Receptor ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Opioid Drugs ◽  
Circuit Components ◽  
Relative Selectivity

AbstractThe medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

scholarly journals Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models

2010 ◽  
Vol 214 (2-3) ◽  
pp. 181-199 ◽  
Author(s):  
Jennifer I. Luebke ◽  
Christina M. Weaver ◽  
Anne B. Rocher ◽  
Alfredo Rodriguez ◽  
Johanna L. Crimins ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Pyramidal Neurons ◽  
Transgenic Mouse Models ◽  
Cortical Pyramidal Neurons

scholarly journals Synapse-specific opioid modulation of thalamo-cortico-striatal circuits

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
William T Birdsong ◽  
Bart C Jongbloets ◽  
Kim A Engeln ◽  
Dong Wang ◽  
Grégory Scherrer ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pyramidal Neurons ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Delta Opioid Receptor ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Opioid Drugs ◽  
Circuit Components ◽  
Relative Selectivity

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

scholarly journals Morphology of Human Nucleus Accumbens Neurons Based on the Immunohistochemical Expression of Gad67

2016 ◽  
Vol 17 (4) ◽  
pp. 297-302
Author(s):  
Maja Sazdanovic ◽  
Slobodanka Mitrovic ◽  
Milos Todorovic ◽  
Maja Vulovic ◽  
Dejan Jeremic ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Pyramidal Neurons ◽  
Immunohistochemical Analysis ◽  
Medium Spiny Neurons ◽  
Immunohistochemical Expression ◽  
Spiny Neurons ◽  
Different Types ◽  
Human Brains

Abstract The nucleus accumbens is a part of the ventral striatum along with the caudate nucleus and putamen. The role of the human nucleus accumbens in drug addiction and other psychiatric disorders is of great importance. The aim of this study was to characterize medium spiny neurons in the nucleus accumbens according to the immunohistochemical expression of GAD67. This study was conducted on twenty human brains of both sexes between the ages of 20 and 75. The expression of GAD67 was assessed immunohistochemically, and the characterization of the neurons was based on the shape and size of the soma and the number of impregnated primary dendrites. We showed that neurons of the human nucleus accumbens expressed GAD67 in the neuron soma and in the primary dendrites. An analysis of the cell body morphology revealed the following four different types of neurons: fusiform neurons, fusiform neurons with lateral dendrites, pyramidal neurons and multipolar neurons. An immunohistochemical analysis showed a strong GAD67 expression in GABAergic medium spiny neurons, which could be classifi ed into four different types, and these neurons morphologically correlated with those described by the Golgi study.

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