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A J Pittman

Publications and source records attributed to A J Pittman.

5 recordsLinked to original sources
PubMed2000

Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures.

Brain-derived neurotrophic factor (BDNF) has been postulated to be a key signaling molecule in regulating synaptic strength and overall circuit activity. In this context, we have found that BDNF dramatically increases the frequency of spontaneously initiated action potentials in hippocampal neurons in dissociated culture. Using analysis of unitary synaptic transmission and immunocytochemical methods, we determined that chronic treatment with BDNF potentiates both excitatory and inhibitory transmission, but that it does so via different mechanisms. BDNF strengthens excitation primarily by augmenting the amplitude of AMPA receptor-mediated miniature EPSCs (mEPSCs) but enhances inhibition by increasing the frequency of mIPSC and increasing the size of GABAergic synaptic terminals. In contrast to observations in other systems, BDNF-mediated increases in AMPA-receptor mediated mEPSC amplitudes did not require activity, because blocking action potentials with tetrodotoxin for the entire duration of BDNF treatment had no effect on the magnitude of this enhancement. These forms of synaptic regulations appear to be a selective action of BDNF because intrinsic excitability, synapse number, and neuronal survival are not affected in these cultures. Thus, although BDNF induces a net increase in overall circuit activity, this results from potentiation of both excitatory and inhibitory synaptic drive through distinct and selective physiological mechanisms.

Action Potentials↗
PubMed1999

In vivo glutamate neurotoxicity is associated with reductions in calcium/calmodulin-dependent protein kinase II immunoreactivity.

Calcium/calmodulin-dependent protein kinase II (CaM kinase) activity is inhibited in cultured hippocampal cells following direct application of glutamate. The goal of the present study was to determine if hippocampal regions that undergo delayed cell death following glutamate microinfusion would exhibit changes in CaM kinase immunoreactivity. Gerbils received bilateral intra-hippocampal infusions of L-glutamate (34 microg/microl), or control treatments of D-glutamate or saline. Animals were sacrificed at 12 or 24 hr to assess cell loss and determine changes in CaM kinase-like immunoreactivity. Hippocampi of gerbils euthanized 12 hr following L-glutamate, or 24 hr following D-glutamate, did not exhibit cell death in the hippocampal CA1 region. Animals injected with L-glutamate and sacrificed 24 hr after infusion had extensive cell damage that was restricted to the hippocampal CA1 region. CaM kinase-like immunoreactivity was absent in the hippocampal CA1 region of all L-glutamate treated animals sacrificed at 12 hr. In these same sections, CaM kinase immunoreactivity was evident in the subiculum, CA2 and CA3 regions. Reduction in CaM kinase immunoreactivity following L-glutamate were also observed using Western analysis. The results confirm and extend the findings of earlier cell culture studies by demonstrating a reduction in CaM kinase immunoreactivity that occurred prior to cell death.

Animals↗
PubMed1999

Induction of electrical excitability by NGF requires autocrine action of a CNTF-like factor.

The overlapping expression of neurotrophin and neural cytokine receptors indicates that most neuronal populations are responsive to both classes of factors, yet relatively little is known about how these two trophic signaling systems interact to regulate neuronal phenotype. We report here that one hallmark of NGF's effects on target cells, the induction of membrane electrical excitability, requires the intermediary action of a CNTF-like factor. We found that NGF's regulation of voltage-gated potassium channels, unlike its regulation of voltage-gated sodium and calcium channels, involves a CNTF-like autocrine/paracrine loop. We showed that NGF induces secretion of a soluble factor that mimics the action of exogenous CNTF in regulating voltage-gated potassium channels and that NGF's ability to regulate this potassium channel is blocked by three independent reagents that inhibit the signaling of CNTF and/or related factors. The identity of this autocrine factor does not appear to be CNTF itself. Thus, a CNTF-like autocrine/paracrine factor is both necessary and sufficient for the regulation of potassium channels by NGF and is a key determinant of the type of electrical excitability that NGF induces in target cells.

Animals↗