Increased GABAergic function in mouse models of Huntington's disease: Reversal by BDNF

Abstract

Huntington's disease (HD) is characterized by loss of striatal gamma-aminobutyric acid (GABA)ergic medium-sized spiny projection neurons (MSSNs), whereas some classes of striatal interneurons are relatively spared. Striatal interneurons provide most of the inhibitory synaptic input to MSSNs and use GABA as their neurotransmitter. We reported previously alterations in glutamatergic synaptic activity in the R6/2 and R6/1 mouse models of HD. In the present study, we used whole-cell voltage clamp recordings to examine GABAergic synaptic currents in MSSNs from striatal slices in these two mouse models compared to those in age-matched control littermates. The frequency of spontaneous GABAergic synaptic currents was increased significantly in MSSNs from R6/2 transgenics starting around 5-7 weeks (when the overt behavioral phenotype begins) and continuing in 9-14-week-old mice. A similar increase was observed in 12-15-month-old R6/1 transgenics. Bath application of brain-derived neurotrophic factor, which is downregulated in HD, significantly reduced the frequency of spontaneous GABAergic synaptic currents in MSSNs from R6/2 but not control mice at 9-14 weeks. Increased GABA current densities also occurred in acutely isolated MSSNs from R6/2 animals. Immunofluorescence demonstrated increased expression of the ubiquitous alpha1 subunit of GABA(A) receptors in MSSNs from R6/2 animals. These results indicate that increases in spontaneous GABAergic synaptic currents and postsynaptic receptor function occur in parallel to progressive decreases in glutamatergic inputs to MSSNs. In conjunction, both changes will severely alter striatal outputs to target areas involved in the control of movement.

The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington's disease mouse model

“…Impaired 5-HT and BDNF signaling is believed to be involved in depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders including Huntington's disease . Other studies have shown that BDNF can protect neurons against insults that occur in the pathogenesis of HD (Bemelmans et al, 1999;Kells et al, 2004;Canals et al, 2004;Cepeda et al, 2004;Pineda et al, 2005;Zuccato et al, 2005;Lynch et al, 2007). These studies suggest that increasing BDNF levels is beneficial in HD.…”

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

“…[41][42][43] Among them, BDNF, so far the best candidate, has been shown to modulate the onset and severity of motor and cognitive functions in HD mouse models 5,18,19,44 and to participate in the disruption of the cortico-striatal glutamatergic transmission that occurs in HD. 45,46 Furthermore, transgenic mice overexpressing BDNF in the cerebral cortex, when cross-mated with R6/1 Conditional release of BDNF in Huntington's disease A Giralt et al mice, improve several morphological and behavioral symptoms. 15 As per these data, the development of a putative neuroprotective therapy based on BDNF could be a successful treatment strategy for the disease.…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…Glutamatergic inputs from the cortex appear to show abnormal increases in activity at the time when symptoms are first apparent, as evidenced by studies showing increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid responsiveness in MSNs from YAC128 HD mice [58], and increased large amplitude synaptic events in MSNs from the R6/2 model [59]. gamma-aminobutyric acid-ergic interneuron populations within the striatum also show abnormalities at this time, with MSNs from the R6/2 model demonstrating increases in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) that appear to originate from these interneuron populations rather than the MSNs themselves [60,61]. Importantly, these changes have consequences for striatal network function, including a reduction in correlated firing of MSNs [62] and the emergence of glutamate-dependent MSN hyperactivity [63].…”

“…These reductions correlate with alterations in synaptic architecture and loss of dendritic spines [59,64], suggesting that in more advanced disease the MSNs become disconnected from glutamatergic corticostriatal inputs. Meanwhile, the gammaaminobutyric acid-ergic interneurons that synapse onto MSNs continue to exert an increased inhibitory effect [60]. One would anticipate that the net effect of these two coincident changes would be a dramatic suppression of MSN function, presumably resulting in more profound motor dysfunction.…”