Selective cortical interneuron and GABA deficits in cyclin D2-null mice

Abstract

In contrast to cyclin D1 nulls (cD1 -/-), mice without cyclin D2 (cD2 -/-) lack cerebellar stellate interneurons; the reason for this is unknown. In the present study in cortex, we found a disproportionate loss of parvalbumin (PV) interneurons in cD2 -/-mice. This selective reduction in PV subtypes was associated with reduced frequency of GABA-mediated inhibitory postsynaptic currents in pyramidal neurons, as measured by voltage-clamp recordings, and increased cortical sharp activity in the EEGs of awake-behaving cD2 -/-mice. Cell cycle regulation was examined in the medial ganglionic eminence (MGE), the major source of PV interneurons in mouse brain, and differences between cD2 -/-and cD1 -/-suggested that cD2 promotes subventricular zone (SVZ) divisions, exerting a stronger inhibitory influence on the p27 Cdk-inhibitor (Cdkn1b) to delay cell cycle exit of progenitors. We propose that cD2 promotes transit-amplifying divisions in the SVZ and that these ensure proper output of at least a subset of PV interneurons.

Loss of COUP-TFI Alters the Balance between Caudal Ganglionic Eminence- and Medial Ganglionic Eminence-Derived Cortical Interneurons and Results in Resistance to Epilepsy

“…Conditional inactivation of COUP-TFI using a pan-interneuronal Cre mouse line leads to increased PV-expressing interneurons and decreased VIP-and CR-expressing bipolar neurons, without affecting the total number of cortical GABAergic cells. Interestingly, COUP-TFI conditional embryos show increased cellular proliferation predominantly in the MGE as well as enhanced expression of the cell cycle gene cyclinD2, known to establish the proper density of PV-expressing interneurons (Glickstein et al, 2007b). Strikingly, we found no discernible electroencephalographic (EEG) abnormalities, but, instead, COUP-TFI conditional mice are more resistant to pharmacologically induced seizures, a GABA-dependent property.…”

“…Thus, increased proliferation, particularly in the MGE region, was detected in COUP-TFI CKO-Dlx5/6 embryos. To further investigate whether cell cycle progression was affected in the absence of COUP-TFI in cortical interneurons, we assessed expression of the G 1 -active cell cycle marker cyclinD2, known to promote SVZ divisions in the telencephalon (Glickstein et al, 2007b). Strikingly, we found that expression of cyclinD2 was increased in SVZ progenitors of E13.5 and E15.5 COUP-TFI CKO-Dlx5/6 embryos, predominantly at rostromedial levels (Fig.…”

“…Previous reports have shown that altered balance of interneuronal subtypes correlate with epileptic phenotypes and disruption of cortical EEG rhythms (Powell et al, 2003;Cobos et al, 2005;Glickstein et al, 2007b;Butt et al, 2008;. We therefore chose to obtain long-lasting recordings of basal EEG activity from adult WT (n ϭ 6) and COUP-TFI CKODlx5/6 mice (n ϭ 8).…”

Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex

“…This has led to the suggestion that cyclin D2 is a key determinant of stellate cell formation, and indeed is required for the developmental "appearance of this sublineage" (Huard et al 1999): This notion seems also supported by the observation that in the forebrain of cyclin D2-deWcient mice, discrete subsets of interneurons are missing (Glickstein et al 2007). However, this cannot be interpreted as an indication that cyclin D2 acts to "specify" a stellate cell-speciWc lineage.…”

“…However, this cannot be interpreted as an indication that cyclin D2 acts to "specify" a stellate cell-speciWc lineage. As pointed out (Huard et al 1999;Glickstein et al 2007), lack of cyclin D2 impedes proliferation, and it is well conceivable that this may lead to an exhaustion of the precursor cell pool from which cerebellar inhibitory interneurons originate before stellate cells-which are known to be born last-are indeed formed. Such an interpretation would be in keeping with the data that document that terminal diVerentiation, including the acquisition and expression of cell type speciWc traits for cerebellar inhibitory interneurons is driven by local cues.…”