Asa Abeliovich

PKCγ mutant mice exhibit mild deficits in spatial and contextual learning

Abstract We are undertaking a genetic approach to investigate the role that synaptic modulation in the mammalian central nervous system plays in learning and memory and to identify relevant molecular components. We have generated mice deficient in the γ isoform of protein kinase C (PKCγ), an enzyme that has previously been implicated in both long-term potentiation (LTP) and learning and memory. These mice have a modified LTP of synaptic transmission in the hippocampus. We demonstrate that PKCγ-mutant mice can learn to carry out hippocampus-dependent tasks, although mild deficits are evident. Thus, hippocampal CA1 LTP induced by the conventional tetanic stimulation is not essential for the mice to exhibit spatial and contextual learning. Furthermore, the modification of hippocampal synaptic plasticity correlates with the learning deficits we observe.

Modified hippocampal long-term potentiation in PKCγ-mutant mice

Abstract Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the γ subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKCγ is not part of the molecular machinery that produces LTP but is a key regulatory component.

Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKCγ mutant mice

It is generally believed that a smooth execution of a compound movement, or motor coordination, requires learning of component movements as well as experience-based refinement of the motor program as a whole. PKC gamma mutant mice display impaired motor coordination but intact eyeblink conditioning, a form of component movement learning. Cerebellar long-term depression, a putative cellular mechanism for component motor learning, is also unimpaired. Thus, PKC gamma mutant mice are defective in refinement of the motor program. In the accompanying paper, we demonstrate that innervation of multiple climbing fibers onto Purkinje cells persists in adulthood in these mutant mice. We propose that this defective elimination of surplus climbing fibers underlies motor discoordination.

Impaired synapse elimination during cerebellar development in PKCγ mutant mice

Abstract PKCγ is highly expressed in Purkinje cells (PCs) but not in other types of neurons in the cerebellum. The expression of PKCγ changes markedly during cerebellar development, being very low at birth and reaching a peak around the third postnatal week. This temporal pattern of PKCγ expression coincides with the developmental transition from multiple to single climbing fiber innervation onto each PC. In adult mutant mice deficient in PKCγ, we found that 41% of PCs are still innervated by multiple climbing fibers, while other aspects of the cerebellum including the morphology and excitatory synaptic transmission of PCs appear normal. Thus, elimination of multiple climbing fiber innervation appears to be specifically impaired in the mutant cerebellum. We suggest that the developmental role of PKCγ may be to act as a downstream element in the signal cascade necessary for the elimination of surplus climbing fiber synapses.

Evidence against a role for metabotropic glutamate receptors in mossy fiber LTP : the use of mutant mice and pharmacological antagonists

We have used a number of approaches to address a possible role of metabotropic glutamate receptors (mGluRs) in mossy fiber long-term potentiation (LTP) in the hippocampus. We have used two types of mutant mice--one lacking the mGluR1 subtype of receptor and one lacking the gamma isoform of protein kinase C. In neither type of mouse did we find any alteration in the magnitude of mossy fiber LTP. We next examined whether mGluRs might modulate the magnitude and/or threshold for the induction of mossy fiber LTP. In these experiments we used tetani that were either just subthreshold or just suprathreshold for generating LTP. The mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine [(+)MCPG] did not convert a subthreshold tetanus into a suprathreshold tetanus, nor did (+)MCPG have any effect on the small amount of LTP that was generated by a just suprathreshold tetanus. Based on our studies, we have been unable to identify a role for mGluRs in mossy fiber LTP.

The gene knockout technology for the analysis of learning and memory, and neural development

Publisher Summary Using the gene knockout technology, this chapter presents an analysis of learning and memory, and neural development. It investigates the molecular substrates of synaptic plasticity by producing mice that lack the γ isoform of Ca 2+ /phospholipid-dependent-protein kinase (PKCγ) using the embryonic stem (ES) cell gene targeting technology. PKC constitutes a family of isoenzymes involved in signal transduction pathways in diverse systems. This enzyme was chosen for the study reviewed in the chapter because pharmacological studies have repeatedly implicated PKC as playing a role in long-term potentiation (LTP). To re-examine the role of N -methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated activity in the establishment of neural patterns in the whisker-to-barrel system, reverse genetics is used to selectively “knock out” the NMDAR1 subunit of the NMDA receptor. The results from this examination show that in the knockout animals, although central targeting and topographic projection of trigeminal afferent appear to be normal and postsynaptic neurons are responsive to the stimulation of primary trigeminal afferent, whisker-specific neural patterns fail to develop in the absence of the NMDA receptor.

Parkinson's disease: Guilt by genetic association

Certain sequence variants of the α-synuclein gene are linked to the risk of Parkinsons disease. An analysis of these variants using gene-editing technology provides a possible explanation for this increased risk. See Letter p.95 Determining how genetic risk variants associated with complex diseases actually contribute to the pathological features of the disease remains a challenge. Non-coding sequences variants have been proposed to act in cis to modulate the expression of disease-linked genes, but it is difficult to test this hypothesis because of the complexity of the diseases linked to these variants. Rudolf Jaenisch and colleagues have developed a genetically controlled system to dissect out the cis-acting effect of allelic variants on the expression of the α-synuclein gene SCNA, which has been linked to Parkinsons disease development.

Retraction Note to: Retraction: Integrative genomics identifies APOE ε4 effectors in Alzheimer’s disease

This corrects the article DOI: 10.1038/nature12415

Retraction: Integrative genomics identifies APOE ε4 effectors in Alzheimer’s disease

This corrects the article DOI: 10.1038/nature12415

Retraction: Integrative genomics identifies APOE [epsi]4 effectors in Alzheimer/'s disease

This corrects the article DOI: 10.1038/nature12415